Alzheimer Abeta Peptide Binding Polypeptide

Abstract

The present disclosure relates to a class of engineered polypeptides having a binding affinity for amyloid .beta. (A.beta.) peptides (in the following referred to as A.beta.), comprising the amino acid sequence EX.sub.2X.sub.3YX.sub.5X.sub.6NLX.sub.9AX.sub.11QLCAX.sub.16IX.sub.18X.su- b.19X.sub.20 ED. The present disclosure also relates to the use of such A.beta. peptide binding polypeptides as therapeutic, prognostic and/or diagnostic agents.

Description

FIELD OF THE INVENTION

[0001] The present disclosure relates to a class of engineered polypeptides having a binding affinity for amyloid .beta. (A.beta.) peptide (in the following referred to as A.beta.). The present disclosure also relates to the use of such A.beta. peptide binding polypeptides as therapeutic, prognostic and/or diagnostic agents.

BACKGROUND

[0002] Many different diseases, such as Alzheimer's disease, type II diabetes, primary and secondary systemic amyloidosis, and familial amyloid polyneuropathy 1, have been recognized as belonging to the growing family of amyloid diseases. All amyloid diseases have in common the presence of extracellular protein aggregates that may or may not be fibrillar.

[0003] Alzheimer's disease (AD) is the leading cause of dementia worldwide, with approximately 35 million people affected. Current treatments for Alzheimer's disease provide only modest symptomatic relief, and there is a great need for therapies that slow the course of the disease and prevent or delay the disease in susceptible individuals. Despite tremendous research efforts during the last decades, there is currently no treatment that significantly alters the course of the disease or efficiently stops its development (Citron (2010) Nat Rev Drug Discov 9(5):387-398). The pathological hallmarks of AD include large extracellular amyloid plaques and intracellular neurofibrillary tangles in the brains of affected individuals (Citron (2010), supra). The main constituents of the amyloid plaques are the 40 and 42 amino acid amyloid beta (A.beta.) peptides. It has been hypothesized that the aggregation process of these peptides into oligomers, protofibrils and fibrils play a pivotal role in the neuropathology of AD. Consequently, therapeutic strategies targeting the production and aggregation, as well as clearance of A.beta. from the brain, are under investigation.

[0004] One promising approach for therapy is based on administration of A.beta.-specific agents that bind directly to A.beta. aggregates in the brain or to free A.beta. peptides in the plasma (peripheral sink mechanism) (Citron (2010), supra). Conventional antibodies have demonstrated the great potential of immunotherapy, but have also been associated with severe side effects, such as Fc-mediated pro-inflammatory immune responses. Additionally, antibodies are large molecules and their size may have negative effect on in vivo biodistribution, including uptake into the brain. Therefore, alternative approaches using engineered antibody alternatives and alternative scaffold proteins without effector functions have been suggested to provide safer and more effective therapies, and smaller scaffold proteins are presumed to transfer across the blood-brain barrier faster than large antibodies.

[0005] Several molecules with affinity for specific targets and different non-antibody based scaffolds have been described in the art. In particular, molecules related to protein Z, derived from domain B of staphylococcal protein A (SPA) (Nilsson B et al (1987) Protein Engineering 1:107-133), have been selected from libraries of randomized protein Z molecules using different interaction targets (see eg WO95/19374; WO00/63243; Nord K et al (1995) Prot Eng 8:601-608; Nord K et al (1997) Nature Biotechnology 15:772-777).

[0006] A protein Z variant denoted Z.sub.A.beta.3, targeting monomeric A.beta. with a 17 nM affinity (Gronwall et al (2007) J Biotechnol 128(1):162-183; Hoyer et al (2008) Proc Natl Acad Sci USA 105(13):5099-5104) has been described. Structural analysis has shown that Z.sub.A.beta.3 binds the A.beta. peptide as a disulfide-linked homodimer (due to an internal cysteine), and that both the disulfide-linked dimeric Z variant and the A.beta. peptide fold upon binding. The A.beta. peptide folds into a .beta.-hairpin structure, allowing the first .alpha.-helices in both Z variant units of the homodimer to adopt .beta.-sheet structures with unstructured N-termini (Hoyer and Hard (2008) J. Mol. Biol. 378(2):398-411; Hoyer et al (2008), supra). In a recent in vivo study using an A.beta. transgenic fruit fly model of AD, Z.sub.A.beta.3 was shown to efficiently inhibit formation of toxic amyloidogenic oligomers and plaques, thereby abolishing the neurotoxic effects and restoring the life span of the flies (Hoyer et al (2008), supra; Luheshi et al (2010) PLoS Biol 8(3):e1000334).

[0007] It has been demonstrated that there is a correlation between the affinity of peripherally administered A.beta. specific agents and the efflux of A.beta. from the brain to the plasma. Since levels of A.beta. peptides in the blood are generally low, it is important to use capturing agents of high affinity for such applications.

[0008] Thus, there is a continued need for agents with a high affinity for A.beta., which can be used as reagents in various assays and processes where such an affinity is needed, such as treatment, diagnosis and prognosis of AD.

SUMMARY OF THE INVENTION

[0009] It is an object of the present disclosure to provide new A.beta. peptide binding agents, which could for example be used for therapeutic, prognostic and diagnostic applications.

[0010] It is an object of the present disclosure to provide a molecule allowing for efficient therapy, targeting various forms of A.beta. peptide related pathologies while alleviating the abovementioned and other drawbacks of current therapies.

[0011] It is furthermore an object of the present disclosure to provide a molecule suitable for prognostic and diagnostic applications.

[0012] These, and other objects which are evident to the skilled person from the present disclosure, are met by the different aspects of the invention as claimed in the appended claims and as generally disclosed herein.

[0013] Thus, in a first aspect of the disclosure, there is provided an A.beta. peptide binding polypeptide, which comprises

[0014] a first moiety comprising a first A.beta. peptide binding motif BM1,

[0015] a second moiety comprising a second A.beta. peptide binding motif BM2, which motifs may be the same or different, and

[0016] a linker, [0017] wherein each one of said binding motifs BM1 and BM2 consists of an amino acid sequence selected from [0018] i) EX.sub.2X.sub.3YX.sub.5X.sub.6NLX.sub.9A X.sub.11QLCAX.sub.16IX.sub.18X.sub.19X.sub.20 ED wherein, independently from each other, [0019] X.sub.2 is selected from I, M, Q, R, T and Y; [0020] X.sub.3 is selected from H and V; [0021] X.sub.5 is selected from F, I and L; [0022] X.sub.6 is selected from P and T; [0023] X.sub.9 is selected from N and T; [0024] X.sub.11 is selected from D and H; [0025] X.sub.16 is selected from F and I; [0026] X.sub.18 is selected from N, Q and R; [0027] X.sub.19 is selected from K and S; and [0028] X.sub.20 is selected from F, I, L and R; [0029] and [0030] ii) an amino acid sequence which has at least 95% identity to the sequence defined in i).

[0031] The above definition of a class of sequence related, A.beta. peptide binding polypeptides is based on a statistical analysis of a number of random polypeptide variants of a truncated dimer ((Z.sub.A.beta.3A12).sub.2; SEQ ID NO:113) of the first generation A.beta. peptide binding polypeptide Z.sub.A.beta.3. As detailed in the background section, this first generation A.beta. peptide binding polypeptide was originally identified based on its interaction with A.beta. peptide in selection experiments, and its binding surface has now been modified to create the variants defined herein. The identified A.beta. peptide binding motifs (BM1 and BM2) correspond to the target binding region of the parent scaffold, which constitutes a .beta. sheet and two a helices when bound to A.beta. peptide.

[0032] As the skilled person will realize, the function of any polypeptide, such as the A.beta. peptide binding capacity of the polypeptide of the present disclosure, is dependent on the tertiary structure of the polypeptide. It is therefore possible to make minor changes to the sequence of amino acids in a polypeptide without affecting the function thereof. Thus, the disclosure encompasses modified variants of the A.beta. peptide binding polypeptide, which have retained A.beta. peptide binding characteristics. In this way, encompassed by the present disclosure is an A.beta. peptide binding polypeptide comprising an amino acid sequence with 95% or greater identity to a polypeptide as defined in i). For example, it is possible that an amino acid residue belonging to a certain functional group of amino acid residues (e.g. hydrophobic, hydrophilic, polar etc) could be exchanged for another amino acid residue from the same functional group.

[0033] In some embodiments, such changes may be made in any position of the sequence of the A.beta. peptide binding polypeptide as disclosed herein. In other embodiments, such changes may be made only in the non-variable positions, also denoted scaffold amino acid residues. In such cases, changes are not allowed in the variable positions, i.e. positions denoted by an "X" in sequence i).

[0034] The term "% identity", as used throughout the specification, may for example be calculated as follows. The query sequence is aligned to the target sequence using the CLUSTAL W algorithm (Thompson et al (1994) Nucleic Acids Research, 22:4673-4680). A comparison is made over the window corresponding to the shortest of the aligned sequences. The shortest of the aligned sequences may in some instances be the target sequence. In other instances, the shortest of the aligned sequences may be the query sequence.

[0035] The amino acid residues at each position are compared and the percentage of positions in the query sequence that have identical correspondences in the target sequence is reported as % identity.

[0036] In one embodiment of the first aspect, there is provided an A.beta. peptide binding polypeptide, wherein, in sequence i) of said binding motifs,

[0037] X.sub.2 is further selected from I, Q, and R;

[0038] X.sub.5 is further selected from F and L;

[0039] X.sub.16 is F; and

[0040] X.sub.20 is further selected from I and L.

[0041] In one embodiment of the first aspect, there is provided an A.beta. peptide binding polypeptide as defined above, wherein sequence i) in BM1 consists of the amino acid sequence

[0042] EX.sub.2X.sub.3YX.sub.5X.sub.6NLX.sub.9A X.sub.11QLCAFIX.sub.18X.sub.19L ED

wherein, independently from each other,

[0043] X.sub.2 is selected from I, M, Q, R and Y;

[0044] X.sub.3 is selected from H and V;

[0045] X.sub.5 is selected from F, I and L;

[0046] X.sub.6 is selected from P and T;

[0047] X.sub.9 is selected from N and T;

[0048] X.sub.11 is selected from D and H;

[0049] X.sub.18 is selected from N, Q and R; and

[0050] X.sub.19 is selected from K and S.

[0051] In one embodiment, in sequence i) in BM1, X.sub.2 is further selected from I and R; and X.sub.5 is further selected from F and L.

[0052] In another embodiment, in sequence i) in BM1, X.sub.2 is further selected from I, Q, R and Y; and X.sub.5 is further selected from F and L.

[0053] In yet another embodiment, in sequence i) in BM1, X.sub.2 is further selected from I and R; and X.sub.18 is further selected from Q and R.

[0054] In still another embodiment, in sequence i) in BM1, X.sub.2 is further selected from I, M and R.

[0055] In a further embodiment, in sequence i) in BM1, X.sub.2 is further selected from I and R; X.sub.3 is V; and X.sub.5 is further selected from F and L.

[0056] In one embodiment, sequence i) in BM1 consists of the amino acid sequence

[0057] EX.sub.2VYX.sub.5X.sub.6NLNA X.sub.11QLCAFIX.sub.18SL ED

wherein, independently from each other,

[0058] X.sub.2 is selected from I, M and R;

[0059] X.sub.5 is selected from F, I and L;

[0060] X.sub.6 is selected from P and T;

[0061] X.sub.11 is selected from D and H; and

[0062] X.sub.18 is selected from N, Q and R.

[0063] In one embodiment of the first aspect, there is provided an A.beta. peptide binding polypeptide as defined above, wherein sequence i) in BM2 consists of the amino acid sequence

[0064] EX.sub.2VYX.sub.5PNLX.sub.9A X.sub.11QLCAX.sub.16IX.sub.18X.sub.19X.sub.20 ED

wherein, independently from each other,

[0065] X.sub.2 is selected from I, M, Q, R and T;

[0066] X.sub.5 is selected from F and L;

[0067] X.sub.9 is selected from N and T;

[0068] X.sub.11 is selected from D and H;

[0069] X.sub.16 is selected from F and I;

[0070] X.sub.18 is selected from N, Q and R;

[0071] X.sub.19 is selected from K and S; and

[0072] X.sub.20 is selected from F, I, L and R.

[0073] In one embodiment, in sequence i) in BM2, X.sub.2 is further selected from I, Q and R; X.sub.16 is F; and X.sub.20 is further selected from I and L.

[0074] In another embodiment, in sequence i) in BM2, X.sub.2 is further selected from R and T; and X.sub.5 is L.

[0075] In yet another embodiment, in sequence i) in BM2, X.sub.2 is R; X.sub.5 is L; X.sub.16 is F; and X.sub.20 is further selected from I and L.

[0076] In still another embodiment, in sequence i) in BM2, X.sub.2 is further selected from I, M, Q and R; X.sub.16 is F; and X.sub.20 is L.

[0077] In a further embodiment, in sequence i) in BM2, X.sub.2 is further selected from I, Q and R; X.sub.16 is F; and X.sub.20 is L.

[0078] In one embodiment, sequence i) in BM2 consists of the amino acid sequence

[0079] EX.sub.2VYX.sub.5X.sub.6NLNA X.sub.11QLCAFIX.sub.18SX.sub.20 ED

wherein, independently from each other,

[0080] X.sub.2 is selected from I, M and R;

[0081] X.sub.5 is selected from F, I and L;

[0082] X.sub.6 is selected from P and T;

[0083] X.sub.11 is selected from D and H;

[0084] X.sub.18 is selected from N, Q and R; and

[0085] X.sub.20 is selected from I and L.

[0086] In additional embodiments of any one of BM1 and BM2 as defined above, X.sub.6 may instead be selected from P, T, R and Y.

[0087] As used herein, the designations "first binding motif" or "BM1" and "second binding motif" or "BM2", as well as the designations "first moiety" and "second moiety" are made for clarity reasons to distinguish between the A.beta. peptide binding motifs and moieties. These designations are not intended to refer to the actual order of the different domains in the polypeptide. Thus, for example, said BM2 or second moiety may without restriction appear N-terminally or C-terminally of said BM1 or first moiety in the A.beta. peptide binding polypeptide.

[0088] Herein, "X.sub.n" and "X.sub.m" are used to indicate amino acid residues in positions n and m in the sequence i) as defined above, wherein n and m are integers which indicate the position of an amino acid residue within said sequence as counted from the N-terminal end of said sequence. For example, X.sub.3 and X.sub.6 indicate the amino acid residue in positions three and six, respectively, from the N-terminal end of sequence i).

[0089] In the embodiments of the first aspect, polypeptides are provided wherein X.sub.n in sequence i) is independently selected from a group of possible residues according to Table 1. The skilled person will appreciate that X.sub.n may be selected from any one of the listed groups of possible residues and that this selection is independent from the selection of amino acid residues in X.sub.m, wherein n.noteq.m. Thus, any of the listed possible residues in position X.sub.n in Table 1 may be independently combined with any of the listed possible residues any other variable position in Table 1.

[0090] The skilled person will appreciate that Table 1 is to be read as follows: In one embodiment according to the first aspect, there is provided a polypeptide wherein amino acid residue "X.sub.n" in sequence i) is selected from "Possible residues". Thus, Table 1 discloses several specific and individualized embodiments of the first aspect of the present disclosure. For example, in one embodiment according to the first aspect, there is provided a polypeptide wherein X.sub.2 in sequence i) is selected from I, M, Q, R and Y, and in another embodiment according to the first aspect, there is provided a polypeptide wherein X.sub.2 in sequence i) is selected from M, Q, R and T. For avoidance of doubt, the listed embodiments may be freely combined in yet other embodiments. For example, one such combined embodiment is a polypeptide in which X.sub.2 is selected from I, M, Q, R and Y, while X.sub.6 is T, and X.sub.18 is selected from Q and R.

TABLE-US-00001 TABLE 1 X.sub.n Possible residues X.sub.2 I, M, Q, R, Y X.sub.2 M, Q, R, T X.sub.2 I, Q, R, Y X.sub.2 I, M, R X.sub.2 T, R X.sub.2 I, M, Q, R X.sub.2 I, R, Y X.sub.2 I, Q, R X.sub.2 I, R X.sub.2 R X.sub.2 I X.sub.3 V X.sub.3 H X.sub.5 F, L X.sub.5 F, I X.sub.5 I X.sub.5 L X.sub.5 F X.sub.6 P X.sub.6 T X.sub.9 N X.sub.9 T X.sub.11 D X.sub.11 H X.sub.16 F X.sub.16 I X.sub.18 Q, R X.sub.18 N, Q X.sub.18 N, R X.sub.18 Q X.sub.18 N X.sub.18 R X.sub.19 K X.sub.19 S X.sub.20 I, L X.sub.20 L

[0091] In one embodiment of the first aspect, there is provided an A.beta. peptide binding polypeptide, wherein at least one of said first and second moieties comprises the amino acid sequence

[0092] X.sub.AGX.sub.B-[BM]

Wherein BM is BM1 or BM2 as defined herein, and, independently of each other,

[0093] X.sub.A is selected from A and S; and

[0094] X.sub.B is selected from G and R.

[0095] In another embodiment, there is provided an A.beta. peptide binding polypeptide, wherein at least one of said first and second moieties comprises a binding module amino acid sequence, Bmod, selected from [0096] iii) [BM]-DX.sub.aSQX.sub.bX.sub.cX.sub.dLLX.sub.e EAKKLX.sub.fX.sub.gX.sub.hQA PX.sub.i wherein BM is BM1 or BM2 as defined above, and, independently of each other,

[0097] X.sub.a is selected from P, Q, R and S;

[0098] X.sub.b is selected from N, Q, R and S;

[0099] X.sub.b is selected from A and S;

[0100] X.sub.d is selected from K, N and E;

[0101] X.sub.e is selected from A, S and C;

[0102] X.sub.f is selected from E, N and S;

[0103] X.sub.g is selected from D, E and S;

[0104] X.sub.h is selected from A and S; and

[0105] X.sub.i is selected from no amino acid, A and K,

and [0106] iv) an amino acid sequence which has at least 97% identity to a sequence defined in iii).

[0107] In one embodiment, sequence iii) of Bmod consists of the amino acid sequence

[0108] [BM]-DX.sub.aSQX.sub.bAX.sub.dLLA EAKKLNDAQA PX.sub.i

wherein [BM] is [BM1] or [BM2] as defined above, and

[0109] X.sub.a is selected from P, Q, R and S;

[0110] X.sub.b is selected from N, Q, R and S;

[0111] X.sub.d is selected from K and N; and

[0112] X.sub.i is selected from no amino acid, A and K.

[0113] In one embodiment, sequence iii) consists of an amino acid sequence selected from:

TABLE-US-00002 [BM]-DPSQSANLLAEAKKLNDAQAP; [BM]-DPSQQANLLAEAKKLNDAQAP; [BM]-DSSQSANLLAEAKKLNDAQAP; [BM]-DPSQQAKLLAEAKKLNDAQAP; [BM]-DPSQNANLLAEAKKLNDAQAP; [BM]-DRSQQANLLAEAKKLNDAQAP; [BM]-DQSQRANLLAEAKKLNDAQAP; [BM]-DQSQQANLLAEAKKLNDAQAP; [BM]-DRSQSANLLAEAKKLNDAQAP; [BM]-DRSQRANLLAEAKKLNDAQAP; and [BM]-DRSQNANLLAEAKKLNDAQAP.

[0114] In a more specific embodiment, said first moiety comprises a Bmod in which sequence iii) is an amino acid sequence selected from

TABLE-US-00003 [BM1]-DPSQSANLLAEAKKLNDAQAPA; [BM1]-DPSQQANLLAEAKKLNDAQAPA; [BM1]-DSSQSANLLAEAKKLNDAQAPA; [BM1]-DPSQRANLLAEAKKLNDAQAPA; [BM1]-DPSQQAKLLAEAKKLNDAQAPA; [BM1]-DPSQNANLLAEAKKLNDAQAPA; and [BM1]-DRSQNANLLAEAKKLNDAQAPA.

[0115] In another specific embodiment, said second moiety comprises a Bmod in which sequence iii) is an amino acid sequence selected from

TABLE-US-00004 [BM2]-DPSQQANLLAEAKKLNDAQAPK; [BM2]-DPSQSANLLAEAKKLNDAQAPK; [BM2]-DRSQQANLLAEAKKLNDAQAPK; [BM2]-DQSQRANLLAEAKKLNDAQAPK; [BM2]-DQSQQANLLAEAKKLNDAQAPK; [BM2]-DPSQRANLLAEAKKLNDAQAPK; [BM2]-DRSQSANLLAEAKKLNDAQAPK; [BM2]-DRSQRANLLAEAKKLNDAQAPK; [BM2]-DSSQSANLLAEAKKLNDAQAPK; and [BM2]-DPSQNANLLAEAKKLNDAQAPK.

[0116] The first aspect of the disclosure also provides an A.beta. peptide binding polypeptide as described above, wherein at least one of said first and second moieties comprises the amino acid sequence

[0117] X.sub.AGX.sub.B-[BMod]

wherein Bmod is as defined above, and, independently of each other,

[0118] X.sub.A is selected from A and S; and

[0119] X.sub.B is selected from G and R.

[0120] In one embodiment, at least one of said first and second moieties comprises an amino acid sequence selected from

TABLE-US-00005 AGG-[BM]-DPSQSANLLAEAKKLNDAQAP; AGG-[BM]-DPSQQANLLAEAKKLNDAQAP; AGG-[BM]-DSSQSANLLAEAKKLNDAQAP; AGG-[BM]-DPSQRANLLAEAKKLNDAQAP; AGR-[BM]-DPSQSANLLAEAKKLNDAQAP; AGG-[BM]-DPSQQAKLLAEAKKLNDAQAP; AGG-[BM]-DPSQNANLLAEAKKLNDAQAP; AGR-[BM]-DPSQQANLLAEAKKLNDAQAP; AGR-[BM]-DRSQQANLLAEAKKLNDAQAP; AGR-[BM]-DQSQRANLLAEAKKLNDAQAP; AGR-[BM]-DQSQQANLLAEAKKLNDAQAP; AGR-[BM]-DPSQRANLLAEAKKLNDAQAP; AGR-[BM]-DRSQSANLLAEAKKLNDAQAP; SGG-[BM]-DPSQSANLLAEAKKLNDAQAP; AGR-[BM]-DRSQRANLLAEAKKLNDAQAP; AGR-[BM]-DPSQNANLLAEAKKLNDAQAP; AGR-[BM]-DSSQSANLLAEAKKLNDAQAP; and AGR-[BM]-DRSQNANLLAEAKKLNDAQAP.

[0121] In one embodiment, said first moiety comprises an amino acid sequence selected from

TABLE-US-00006 AGG-[BM1]-DPSQSANLLAEAKKLNDAQAPA; AGG-[BM1]-DPSQQANLLAEAKKLNDAQAPA; AGG-[BM1]-DSSQSANLLAEAKKLNDAQAPA; AGG-[BM1]-DPSQRANLLAEAKKLNDAQAPA; AGR-[BM1]-DPSQSANLLAEAKKLNDAQAPA; AGG-[BM1]-DPSQQAKLLAEAKKLNDAQAPA; and AGG-[BM1]-DPSQNANLLAEAKKLNDAQAPA; AGR-[BM1]-DPSQNANLLAEAKKLNDAQAP; AGR-[BM1]-DSSQSANLLAEAKKLNDAQAP; and AGR-[BM1]-DRSQNANLLAEAKKLNDAQAP.

[0122] In one embodiment, said second moiety comprises an amino acid sequence selected from

TABLE-US-00007 AGR-[BM2]-DPSQQANLLAEAKKLNDAQAPK; AGR-[BM2]-DPSQSANLLAEAKKLNDAQAPK; AGR-[BM2]-DRSQQANLLAEAKKLNDAQAPK; AGR-[BM2]-DQSQRANLLAEAKKLNDAQAPK; AGR-[BM2]-DQSQQANLLAEAKKLNDAQAPK; AGR-[BM2]-DPSQRANLLAEAKKLNDAQAPK; AGR-[BM2]-DRSQSANLLAEAKKLNDAQAPK; AGG-[BM2]-DPSQSANLLAEAKKLNDAQAPK; SGG-[BM2]-DPSQSANLLAEAKKLNDAQAPK; AGR-[BM2]-DRSQRANLLAEAKKLNDAQAPK; AGG-[BM2]-DSSQSANLLAEAKKLNDAQAPK; and AGG-[BM2]-DPSQNANLLAEAKKLNDAQAPK.

[0123] Similarly to the discussion above in relation to sequence i), "X.sub.y" and "X.sub.z" are used herein to indicate amino acid residues in positions y and z in the sequences defined above, wherein y and z represent letters A, B and a-i which indicate the position of variable amino acid residues within said sequence counted from the N-terminal end of said sequence. For example, X.sub.a and X.sub.b indicate the first and second variable amino acid residue, respectively, counted from the N-terminal end of sequence iii), but do not have to be in positions one and two in the amino acid sequence.

[0124] In embodiments according to the first aspect, there are provided polypeptides wherein the variable amino acid residues X.sub.y are independently selected from a group of possible residues according to Table 2. The skilled person will appreciate that X.sub.y may be selected from any one of the listed groups of possible residues and that this selection is independent from the selection of amino acids in X.sub.z, wherein y.noteq.z. Thus, any of the listed possible residues in position X.sub.y in Table 2 may be independently combined with any of the listed possible residues in any other variable position in Table 2.

[0125] The skilled person will appreciate that Table 2 is to be read as follows: In one embodiment according to the first aspect, there is provided a polypeptide wherein amino acid residue "X.sub.y" is selected from "Possible residues". Thus, Table 2 discloses several specific and individualized embodiments of the first aspect of the present disclosure.

TABLE-US-00008 TABLE 2 X.sub.y Possible residues X.sub.A A X.sub.A S X.sub.B G X.sub.B R X.sub.a P, Q, R X.sub.a P, R, S X.sub.a P, R X.sub.a P, Q X.sub.a P, S X.sub.a P X.sub.a R X.sub.a S X.sub.a Q X.sub.b Q, R, S X.sub.b N, R, S X.sub.b R, S X.sub.b R, Q X.sub.b Q, S X.sub.b N, S X.sub.b N X.sub.b Q X.sub.b R X.sub.b S X.sub.c A X.sub.c S X.sub.d N X.sub.d K X.sub.d E X.sub.e A X.sub.e S X.sub.e C X.sub.f E X.sub.f N X.sub.f S X.sub.g D X.sub.g E X.sub.g S X.sub.h A X.sub.h S X.sub.i A X.sub.i K X.sub.i no amino acid

[0126] Additionally, Table 3 lists possible combinations of 2, 3 or 6 of X.sub.A-B and X.sub.a-i. The skilled person will appreciate that these combinations may be independently combined with any of the listed possible residues in any other variable position in Table 2.

TABLE-US-00009 TABLE 3 Possible X.sub.y residues X.sub.AX.sub.B AG, AR X.sub.AX.sub.B AG X.sub.AX.sub.B AR X.sub.fX.sub.g EE, ES, SD, SE, SS, ND X.sub.fX.sub.g ES X.sub.fX.sub.g SE X.sub.fX.sub.g SD X.sub.fX.sub.g ND X.sub.aX.sub.bX.sub.d PQN, PSN, PQK, QRN, SSN X.sub.aX.sub.bX.sub.d PQN, PSN, QRN X.sub.aX.sub.bX.sub.d PQN, PSN X.sub.aX.sub.bX.sub.d PSN X.sub.aX.sub.bX.sub.d PQN X.sub.aX.sub.bX.sub.d QRN X.sub.aX.sub.bX.sub.d PQK X.sub.aX.sub.bX.sub.d SSN X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX; AGPQNA, AGPSNA, ARPSNA, AGPQKA, ARQRNK, ARPSNK, ARPQNK, AGPSNK, ARSSNA AGSSNK X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i AGPQNA, ARPSNA, AGPSNA, ARQRNK, AGPSNK X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i AGPQNA, ARQPKK X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i AGPQNA X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i AGPSNA X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i ARPSNA X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i AGPQKA X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i ARQRNK X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i ARPSNK X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i ARPQNK X.sub.AX.sub.BX.sub.aX.sub.bX.sub.dX.sub.i AGPSNK X.sub.cX.sub.dX.sub.eX.sub.fX.sub.dX.sub.h ANANDA X.sub.cX.sub.dX.sub.eX.sub.fX.sub.dX.sub.h ANASEA X.sub.cX.sub.dX.sub.eX.sub.fX.sub.dX.sub.h ANASDA X.sub.bX.sub.dX.sub.eX.sub.fX.sub.gX.sub.h SESNDS X.sub.bX.sub.dX.sub.eX.sub.fX.sub.gX.sub.h SESSES X.sub.bX.sub.dX.sub.eX.sub.fX.sub.gX.sub.h SESSDS X.sub.bX.sub.dX.sub.eX.sub.fX.sub.gX.sub.h SECNDS X.sub.bX.sub.dX.sub.eX.sub.fX.sub.gX.sub.h SECSES X.sub.bX.sub.dX.sub.eX.sub.fX.sub.gX.sub.h SECSDS

[0127] As discussed above, polypeptides comprising minor changes as compared to the above amino acid sequences, which changes do not largely affect the tertiary structure or function of the polypeptide, are also within the scope of the present disclosure. Thus, sequence iv) has at least 97% identity to a sequence defined by iii).

[0128] In one embodiment of the A.beta. peptide binding polypeptide according to the first aspect of the disclosure, the definitions above are subject to the proviso that at least one of the first and second moiety of the polypeptide does not comprise an amino acid sequence selected from

TABLE-US-00010 (SEQ ID NO: 554) VDNKFNKEGK GAPGEIHYLP NLNADQLCAF IRSLEDDPSQ SANLLAEAKK LNDAQAPK and (SEQ ID NO: 555) VDNKFNKEIE VATGEIVYLP NLNADQLCAF INSLEDDPSQ SANLLAEAKK LNDAQAPK.

[0129] As stated above, the A.beta. peptide binding polypeptide according to the first aspect comprises a linker. In one embodiment, said linker is arranged between said first moiety and said second moiety as defined herein.

[0130] The skilled person is aware of different kinds of linkers with different properties, such as flexible amino acid linkers, rigid amino acid linkers and cleavable amino acid linkers. Linkers have been used to for example increase stability or improve folding of fusion proteins, to increase expression, improve biological activity, enable targeting and alter pharmacokinetics of fusion proteins.

[0131] Flexible linkers are often used when the joined domains require a certain degree of movement or interaction, and may be particularly useful in some embodiments of the A.beta. peptide binding polypeptide as defined herein. Such linkers are generally composed of small, non-polar (for example G) or polar (for example S or T) amino acids. Some flexible linkers primarily consist of stretches of G and S residues, for example (GGGGS).sub.p and (SSSSG).sub.p. Adjusting the copy number "p" allows for optimization of the linker in order to achieve appropriate separation between the functional moieties or to maintain necessary inter-moiety interaction. Apart from G and S linkers, other flexible linkers are known in the art, such as G and S linkers containing additional amino acid residues, such as T, A, K and E, to maintain flexibility, as well as polar amino acid residues to improve solubility.

[0132] In one embodiment of the first aspect disclosed herein, the linker is a flexible linker comprising at least one amino acid residue selected from the group consisting of glycine (G), serine (S) and threonine (T). In one embodiment, said linker has a general formula selected from (G.sub.nS.sub.m).sub.p and (S.sub.nG.sub.m).sub.p, wherein, independently, n=1-7, m=0-7, n+m.ltoreq.8 and p=1-10. In one embodiment, n=1-5. In one embodiment, m=0-5. In one embodiment, p=1-5. In one embodiment, said linker is selected from the group consisting of S.sub.4G, (S.sub.4G).sub.3, (S.sub.4G).sub.4 and (S.sub.4G).sub.8. In one embodiment, said linker is selected from the group consisting of S.sub.4G, (S.sub.4G).sub.2, (S.sub.4G).sub.3 and (S.sub.4G).sub.4. In a more specific embodiment, n=4, m=1 and p=2-3. In one embodiment, said linker is selected from the group consisting of (S.sub.4G).sub.2 and (S.sub.4G).sub.3. In one embodiment, said linker is (S.sub.4G).sub.2. In one embodiment, said linker is (S.sub.4G).sub.3.

[0133] In another embodiment of the first aspect of the present disclosure, there is provided an A.beta. peptide binding polypeptide as defined herein, in which said linker comprises an amino acid sequence selected from the group consisting of VEVDNKFNKEMAS, VDNKFNKEMAS, VEVDNKFNKE, VDNKFNKE, AEAKYAKE, ADNNFNK, ADNKFNK, ADAQQNNFNK, AQHDE, VDNKFNK, AEAKYAK, VDAKYAK and ADAKYAK. In one embodiment, said sequence is selected from VEVDNKFNKEMAS and VDNKFNKEMAS. In one embodiment, said sequence is selected from VEVDNKFNKE and VDNKFNKE. In one embodiment, said sequence is VEVDNKFNKEMAS. In another embodiment, said sequence is VEVDNKFNKE.

[0134] The skilled person will appreciate that the properties of the linker will generally not be changed by the addition of a small number of amino acid residues to its N- or C-terminus. Thus, in a further embodiment, said linker further comprises 1-5 additional amino acid residues at the N- or C-terminal end of said linker, such as 1-4 additional amino acid residues, such as 1-3 additional amino acid residues, such as 3 additional amino acid residues. In one embodiment, said additional amino acid residues are selected from the group consisting of AS, MAS and RAS. In one embodiment, said additional amino acid residues are RAS. In one embodiment, said additional amino acid residues are MAS.

[0135] The skilled person will appreciate that the presence of a linker arranged in any of the contexts mentioned above does not exclude the presence of additional linkers in the same or any other context. Thus, in one embodiment, the A.beta. peptide binding polypeptide as defined herein further comprises at least one additional linker, such as a linker selected from the group consisting of flexible amino acid linkers, rigid amino acid linkers and cleavable amino acid linkers. In one embodiment, said linker is arranged between the A.beta. peptide binding polypeptide as disclosed herein and a second or further part consisting of a polypeptide having a desired biological activity. Further below is a general discussion of alternatives for such a second part.

[0136] The skilled person will appreciate that the A.beta. peptide binding polypeptides as disclosed herein may comprise any first moiety in combination with any second moiety. Thus, the presence of one particular first moiety as disclosed herein does neither limit the choice of second moiety nor the choice of linker as disclosed herein, and vice versa. The skilled person will appreciate that first moiety, second moiety and linker as disclosed herein may be independently combined.

[0137] As described in detail in the experimental section to follow, the selection of A.beta. peptide binding polypeptides led to the identification of a number of individual A.beta. peptide binding motifs (BM1 and BM2). These motifs constitute individual embodiments of sequence i) according to this aspect. The A.beta. peptide binding motifs BM1 and BM2 of the A.beta. peptide correspond to amino acid residues 4-25 and 64-85, respectively, in the sequences with SEQ ID NO:1-17, 19-106 and 118-553, and to amino acid residues 4-25 and 69-90, respectively, in SEQ ID NO:18, all as presented in FIG. 1. Hence, in one embodiment of the A.beta. peptide binding polypeptide as defined herein, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:1-106 and 118-553, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:1-17, 19-106 and 118-553 or to amino acid residues 69-90 in SEQ ID NO:18. In another embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:1-106, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:1-17 and 19-106 or to amino acid residues 69-90 in SEQ ID NO:18. In another embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159 or to amino acid residues 69-90 in SEQ ID NO:18. In another embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104 or to amino acid residues 69-90 in SEQ ID NO:18. In another embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159 or to amino acid residues 69-90 in SEQ ID NO:18. In another embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:18, 51, 55, 59, 64, 70, 78, 95 and 118-142, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:51, 55, 59, 64, 70, 78, 95 and 118-142 or to amino acid residues 69-90 in SEQ ID NO:18. In another embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:18, 55, 70, 95, 124-127, 130-133, 139 and 140, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:55, 70, 95, 124-127, 130-133, 139 and 140 or to amino acid residues 69-90 in SEQ ID NO:18. In another embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:18, 55, 70, 95, 124, 125, 132, 133, 139 and 140, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:55, 70, 95, 124, 125, 132, 133, 139 and 140 or to amino acid residues 69-90 in SEQ ID NO:18. In another embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:18, 28, 35, 49, 50, 70, 84 and 95, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:28, 35, 49, 50, 70, 84 and 95 or to amino acid residues 69-90 in SEQ ID NO:18. In one embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:18, 70 and 95, while sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:70 and 95 or amino acid residues 69-90 in SEQ ID NO:18. In one particular embodiment, sequence i) of BM1 corresponds to amino acid residues 4-25 in SEQ ID NO:95 and sequence i) of BM2 corresponds to amino acid residues 64-85 in SEQ ID NO:95.

[0138] In another embodiment, there is provided an A.beta. peptide binding polypeptide as disclosed herein, wherein the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:1-106 and 118-553 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:1-17, 19-106 and 118-553 or amino acid residues 66-90 in SEQ ID NO:18. In another embodiment, there is provided an A.beta. peptide binding polypeptide as disclosed herein, wherein the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:1-106 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:1-17 and 19-106 or amino acid residues 66-90 in SEQ ID NO:18. In another embodiment, the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159 or amino acid residues 66-90 in SEQ ID NO:18. In another embodiment, the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104 or amino acid residues 66-90 in SEQ ID NO:18. In another embodiment, the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159 or amino acid residues 66-90 in SEQ ID NO:18. In another embodiment, the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:18, 51, 55, 59, 64, 70, 78, 95 and 118-142 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:51, 55, 59, 64, 70, 78, 95 and 118-142 or amino acid residues 66-90 in SEQ ID NO:18. In another embodiment, the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:18, 55, 70, 95, 124-127, 130-133, 139 and 140 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:55, 70, 95, 124-127, 130-133, 139 and 140 or amino acid residues 66-90 in SEQ ID NO:18. In another embodiment, the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:18, 55, 70, 95, 124, 125, 132, 133, 139 and 140 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:55, 70, 95, 124, 125, 132, 133, 139 and 140 or amino acid residues 66-90 in SEQ ID NO:18. In yet another embodiment, the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:18, 28, 35, 49, 50, 70, 84 and 95 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:28, 35, 49, 50, 70, 84 and 95 or amino acid residues 66-90 in SEQ ID NO:18. In one embodiment, the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:18, 70 and 95 and the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:70 and 95 or amino acid residues 66-90 in SEQ ID NO:18. In one particular embodiment, the first moiety comprises amino acid residues 1-25 in SEQ ID NO:95 and the second moiety comprises amino acid residues 61-85 in SEQ ID NO:95.

[0139] In another embodiment, there is provided an A.beta. peptide binding polypeptide as disclosed herein having a binding module, Bmod, as defined above, wherein sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:1-106 and 118-553, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:1-17, 19-106 and 118-553 or amino acid residues 69-112 in SEQ ID NO:18. In another embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:1-106, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:1-17 and 19-106 or amino acid residues 69-112 in SEQ ID NO:18. In another embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159 or amino acid residues 69-112 in SEQ ID NO:18. In another embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104 or amino acid residues 69-112 in SEQ ID NO:18. In another embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159 or amino acid residues 69-112 in SEQ ID NO:18. In another embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:18, 51, 55, 59, 64, 70, 78, 95 and 118-142, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:51, 55, 59, 64, 70, 78, 95 and 118-142 or amino acid residues 69-112 in SEQ ID NO:18. In another embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:18, 55, 70, 95, 124-127, 130-133, 139 and 140, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:55, 70, 95, 124-127, 130-133, 139 and 140 or amino acid residues 69-112 in SEQ ID NO:18. In another embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:18, 55, 70, 95, 124, 125, 132, 133, 139 and 140, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:55, 70, 95, 124, 125, 132, 133, 139 and 140 or amino acid residues 69-112 in SEQ ID NO:18. In yet another embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:18, 28, 35, 49, 50, 70, 84 and 95, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:28, 35, 49, 50, 70, 84 and 95 or amino acid residues 69-112 in SEQ ID NO:18. In one embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:18, 70 and 95, while sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in any one of SEQ ID NO:70 and 95 or amino acid residues 69-112 in SEQ ID NO:18. In one particular embodiment, sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in SEQ ID NO:95 and sequence iii) in Bmod of the second moiety comprises amino acid residues 64-107 in SEQ ID NO:95.

[0140] As discussed above, the skilled person will appreciate that the 22 amino acid residue binding motifs, BM, as well as the various stretches of 25, 44 or 47 amino acid residues as defined herein and all comprising a BM, may all be combined independently. For example, the BM or a 25 amino acid residue stretch comprising a BM, may be grafted into another amino acid environment than that of the original polypeptide, which new environment substantially retains the three-dimensional structure of the original environment. Thus, in another embodiment of the A.beta. peptide binding polypeptide as disclosed herein, there is provided a A.beta. peptide binding polypeptide wherein the first moiety comprises an amino acid sequence corresponding to amino acid residues 4-25, 1-25, 4-47 or 1-47 from any one of SEQ ID NO:1-106 and 118-553; and the second moiety comprises an amino acid sequence corresponding to amino acid residues 64-85, 61-85, 64-107 or 61-107 from any one of SEQ ID NO:1-17, 19-106 and 118-553 or to amino acid residues 69-90, 66-90, 69-112 or 66-112 from SEQ ID NO:18, and wherein both amino acid sequences comprised in each of the first and second moieties are from the same SEQ ID NO. Also, in another embodiment of the A.beta. peptide binding polypeptide as disclosed herein, there is provided a A.beta. peptide binding polypeptide wherein the first moiety comprises an amino acid sequence corresponding to amino acid residues 4-25, 1-25, 4-47 or 1-47 from any one of SEQ ID NO:1-106; and the second moiety comprises an amino acid sequence corresponding to amino acid residues 64-85, 61-85, 64-107 or 61-107 from any one of SEQ ID NO:1-17 and 19 to 106; or to amino acid residues 69-90, 66-90, 69-112 or 66-112 from SEQ ID NO:18, and wherein both amino acid sequences comprised in each of the first and second moieties are from the same SEQ ID NO.

[0141] In another embodiment according to this aspect of the disclosure, there is provided an A.beta. peptide binding polypeptide, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-106 and 118-553; such as from the group consisting of SEQ ID NO:1-106; such as from the group consisting of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159; such as from the group consisting of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104; such as from the group consisting of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159; such as from the group consisting of SEQ ID NO:18, 51, 55, 59, 64, 70, 78, 95 and 118-142; such as from the group consisting of SEQ ID NO:18, 55, 70, 95, 124-127, 130-133, 139 and 140; such as from the group consisting of SEQ ID NO:18, 55, 70, 95, 124, 125, 132, 133, 139 and 140; such as from the group consisting of SEQ ID NO:18, 28, 35, 49, 50, 70, 84 and 95; such as from the group consisting of SEQ ID NO 18, 70 and 95. In one embodiment, the A.beta. peptide binding polypeptide comprises SEQ ID NO:95.

[0142] "Amyloid .beta.", "A.beta." or ".beta.-amyloid" as used herein refer to amyloid .beta. proteins and peptides, amyloid .beta. precursor protein (APP), as well as modifications, fragments and functional equivalents thereof. In particular, by "amyloid .beta. peptide" or "A.beta. peptide" is meant any fragment produced by proteolytic cleavage of APP, especially fragments which are involved in or associated with the amyloid pathologies. Such fragments include, but are not limited to, A.beta..sub.1-38, A.beta..sub.1-39, A.beta..sub.1-40, A.beta..sub.1-41, A.beta..sub.1-42 and A.beta..sub.1-43.

[0143] The terms "A.beta. peptide binding" and "binding affinity for A.beta. peptide" as used in this specification refer to a property of a polypeptide which may be tested for example by ELISA or by use of surface plasmon resonance (SPR) technology.

[0144] For example as described in the examples below, A.beta. peptide binding affinity may be tested in an experiment in which samples of the polypeptide are captured on antibody coated ELISA plates and biotinylated A.beta. peptide is added, followed by streptavidin conjugated HRP. TMB substrate is added and the absorbance at 450 nm is measured using a multi-well plate reader, such as Victor.sup.3 (Perkin Elmer). The skilled person may then interpret the results obtained by such experiments to establish at least a qualitative measure of the binding affinity of the polypeptide for A.beta. peptide. If a quantitative measure is desired, for example to determine the EC50 value (the half maximal effective concentration) for the interaction, ELISA may also be used. The response of the polypeptides against a dilution series of biotinylated A.beta. peptide is measured using ELISA as described above. The skilled person may then interpret the results obtained by such experiments and EC50 values may be calculated from the results using for example GraphPad Prism 5 and non-linear regression.

[0145] A.beta. peptide binding affinity may also be tested in an experiment in which A.beta. peptide, or a fragment thereof, is immobilized on a sensor chip of a surface plasmon resonance (SPR) instrument, and the sample containing the polypeptide to be tested is passed over the chip. Alternatively, the polypeptide to be tested is immobilized on a sensor chip of the instrument, and a sample containing A.beta. peptide, or a fragment thereof, is passed over the chip. The skilled person may then interpret the results obtained by such experiments to establish at least a qualitative measure of the binding affinity of the polypeptide for A.beta. peptide. If a quantitative measure is desired, for example to determine a K.sub.D value for the interaction, surface plasmon resonance methods may also be used. Binding values may for example be defined in a Biacore (GE Healthcare) or ProteOn XPR 36 (Bio-Rad) instrument. A.beta. peptide is suitably immobilized on a sensor chip of the instrument, and samples of the polypeptide whose affinity is to be determined are prepared by serial dilution and injected in random order. K.sub.D values may then be calculated from the results using for example the 1:1 Langmuir binding model of the BIAevaluation 4.1 software, or other suitable software, provided by the instrument manufacturer.

[0146] In one embodiment, the A.beta. peptide binding polypeptide is capable of binding to A.beta. peptide such that the EC50 value of the interaction is at most 1.times.10.sup.-7 M, such as at most 1.times.10.sup.-8 M, such as at most 1.times.10.sup.-9 M, such as at most 1.times.10.sup.-19 M.

[0147] In one embodiment, the A.beta. peptide binding polypeptide is capable of binding to A.beta. peptide such that the K.sub.D value of the interaction is at most 1.times.10.sup.-7 M, such as at most 1.times.10.sup.-8 M, such as at most 1.times.10.sup.-9 M, such as at most 1.times.10.sup.-19 M.

[0148] The skilled person will understand that various modifications and/or additions can be made to an A.beta. peptide binding polypeptide according to the first aspect disclosed herein in order to tailor the polypeptide to a specific application without departing from the scope of the present disclosure.

[0149] For example, in one embodiment there is provided a fragment of an A.beta. peptide binding polypeptide as disclosed herein, which fragment retains binding affinity for an A.beta. peptide.

[0150] An A.beta. peptide binding polypeptide encompassed by the present disclosure may comprise a number of additional amino acid residues. For example, in one embodiment, there is provided an A.beta. peptide binding polypeptide as described herein, which polypeptide has been extended by and/or comprises at least one additional amino acid at at least one of the N terminus and the C terminus. Such a polypeptide should be understood as a polypeptide having one or more additional amino acid residues at the very first and/or the very last position in the polypeptide chain. Thus, an A.beta. peptide binding polypeptide may comprise any suitable number of additional amino acid residues, for example at least one additional amino acid residue. Suitably, an A.beta. peptide binding polypeptide with additional amino acids will retain binding affinity for an A.beta. peptide.

[0151] Each additional amino acid residue may individually or collectively be added in order to, for example, improve or simplify production, purification, stabilization in vivo or in vitro, coupling or detection of the polypeptide. Such additional amino acid residues may for example comprise one or more amino acid residues added for the purpose of chemical coupling. One example of this is the addition of a cysteine residue. Additional amino acid residues may also provide a "tag" for purification or detection of the polypeptide, such as a His.sub.6 tag, a (HisGlu).sub.3 tag ("HEHEHE" tag) or a "myc" (c-myc) tag or a "FLAG" tag for interaction with antibodies specific to the tag or immobilized metal affinity chromatography (IMAC) in the case of the His.sub.6-tag.

[0152] The further amino acids as discussed above may be coupled to the A.beta. peptide binding polypeptide by means of chemical conjugation (using known organic chemistry methods) or by any other means, such as expression of the A.beta. peptide binding polypeptide as a fusion protein or joined in any other fashion, either directly or via a linker, for example an amino acid linker as discussed above.

[0153] Fusion proteins, or conjugates, in which an A.beta. peptide binding polypeptide described herein constitutes a first domain (herein referred to as a first part), and which also comprises second and optionally further domains (herein referred to as second and further parts) are also contemplated and fall within the ambit of the present disclosure. The second and optional further parts of the fusion polypeptide or conjugate suitably have a desired biological activity.

[0154] For example, such a desired biological activity could be binding to the same target, A.beta. peptide, as the first part. In one embodiment, this second and optional further A.beta. peptide binding part could comprise one or more additional polypeptides as disclosed in the first aspect above, making the fusion protein or conjugate a multimer (such as a dimer, trimer, tetramer etc) of A.beta. peptide binding polypeptides as disclosed herein. The amino acid sequences of the individual, "monomer", polypeptide chains may be the same or different. Also contemplated are constructs in which the first part is as disclosed in the first aspect, whereas the second and optional further parts are not.

[0155] Thus, in a second aspect of the present disclosure, there is provided a fusion protein or a conjugate, comprising a first part consisting of an A.beta. peptide binding polypeptide according to the first aspect, and a second part consisting of a polypeptide having a desired biological activity. In one embodiment, said fusion protein or conjugate may additionally comprise further parts, comprising desired biological activities that can be either the same or different from the biological activity of the first and/or second part. For the sake of clarity, the discussion to follow relating to said second part is equally relevant for any further parts which may be present in the fusion or conjugate as defined herein.

[0156] Non-limiting examples of a desired biological activity comprise a therapeutic activity, a binding activity and an enzymatic activity.

[0157] In one embodiment, the second part having a desired biological activity is a therapeutically active polypeptide.

[0158] Non-limiting examples of therapeutically active polypeptides are biomolecules, such as molecules selected from the group consisting of human endogenous enzymes, hormones, growth factors, chemokines, cytokines and lymphokines.

[0159] Non-limiting examples of binding activities are binding activities which increase the in vivo half-life of the fusion protein or conjugate. In one particular embodiment, said binding activity which increases the in vivo half-life of the fusion protein or conjugate is an albumin binding activity. In one embodiment, said albumin binding activity is provided by the albumin binding domain of streptococcal protein G or a derivative thereof, for example comprising the amino acid sequence SEQ ID NO:107 or a derivative thereof. In another particular embodiment, said binding activity which increases the in vivo half-life of the fusion protein or conjugate is an FcRn binding activity. FcRn binding may for example be provided by an antibody or a fragment thereof having FcRn affinity (reviewed in Roopenian and Akilesh (2007), Nat Rev Immunol 7:715-725), or by a Z variant with engineered affinity for FcRn (Seijsing et al (2014), Proc Natl Acad Sci USA 111:17110-5).

[0160] A binding activity as discussed above may be a binding activity that acts to block a biological activity or a binding activity that acts to stimulate a biological activity. Specific, contemplated targets for binding of a second or optional further part are selected from the group consisting of Tau, apolipoprotein E (ApoE), beta-secretase 1 (BACE1), gamma-secretase, transferrin receptor (TfR), complement factor C1s, presenilin 1, presenilin 2, nicastrin, alpha-synuclein and Bri.

[0161] In one particular embodiment, the second part of said fusion protein or conjugate may comprise an antibody or an antigen binding fragment thereof. As is well known, antibodies are immunoglobulin molecules capable of specific binding to a target (an antigen), such as a carbohydrate, polynucleotide, lipid, polypeptide or other, through at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody or an antigen binding fragment thereof" encompasses not only full-length or intact polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof, such as Fab, Fab', F(ab').sub.2, Fab.sub.3, Fv and variants thereof, fusion proteins comprising one or more antibody portions, humanized antibodies, chimeric antibodies, minibodies, diabodies, triabodies, tetrabodies, linear antibodies, single chain antibodies, multispecific antibodies (e.g., bispecific antibodies) and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies and covalently modified antibodies. Further examples of modified antibodies and antigen binding fragments thereof include nanobodies, AlbudAbs, DARTs (dual affinity re-targeting), BiTEs (bispecific T-cell engager), TandAbs (tandem diabodies), DAFs (dual acting Fab), two-in-one antibodies, SMIPs (small modular immunopharmaceuticals), FynomAbs (fynomers fused to antibodies), DVD-Igs (dual variable domain immunoglobulin), CovX-bodies (peptide modified antibodies), duobodies and triomAbs. This listing of variants of antibodies and antigen binding fragments thereof is not to be seen as limiting, and the skilled person is aware of other suitable variants.

[0162] A full-length antibody comprises two heavy chains and two light chains. Each heavy chain contains a heavy chain variable region (V.sub.H) and first, second and third constant regions (C.sub.H1, C.sub.H2 and C.sub.H3). Each light chain contains a light chain variable region (V.sub.L) and a light chain constant region (C.sub.L). Depending on the amino acid sequence of the constant domain of its heavy chains, antibodies are assigned to different classes. There are six major classes of antibodies: IgA, IgD, IgE, IgG, IgM and IgY, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The term "full-length antibody" as used herein refers to an antibody of any class, such as IgD, IgE, IgG, IgA, IgM or IgY (or any sub-class thereof). The subunit structures and three-dimensional configurations of different classes of antibodies are well known.

[0163] An "antigen binding fragment" is a portion or region of an antibody molecule, or a derivative thereof, that retains all or a significant part of the antigen binding of the corresponding full-length antibody. An antigen binding fragment may comprise the heavy chain variable region (V.sub.H), the light chain variable region (V.sub.L), or both. Each of the V.sub.H and V.sub.L typically contains three complementarity determining regions CDR1, CDR2 and CDR3. The three CDRs in V.sub.H or V.sub.L are flanked by framework regions (FR1, FR2, FR3 and FR4). As briefly listed above, examples of antigen binding fragments include, but are not limited to: (1) a Fab fragment, which is a monovalent fragment having a V.sub.L-C.sub.L chain and a V.sub.H-C.sub.H1 chain; (2) a Fab' fragment, which is a Fab fragment with the heavy chain hinge region, (3) a F(ab').sub.2 fragment, which is a dimer of Fab' fragments joined by the heavy chain hinge region, for example linked by a disulfide bridge at the hinge region; (4) an Fc fragment; (5) an Fv fragment, which is the minimum antibody fragment having the V.sub.L and V.sub.H domains of a single arm of an antibody; (6) a single chain Fv (scFv) fragment, which is a single polypeptide chain in which the V.sub.H and V.sub.L domains of an scFv are linked by a peptide linker; (7) an (scFv).sub.2, which comprises two V.sub.H domains and two V.sub.L domains, which are associated through the two V.sub.H domains via disulfide bridges and (8) domain antibodies, which can be antibody single variable domain (V.sub.H or V.sub.L) polypeptides that specifically bind antigens.

[0164] Antigen binding fragments can be prepared via routine methods. For example, F(ab').sub.2 fragments can be produced by pepsin digestion of a full-length antibody molecule, and Fab fragments can be generated by reducing the disulfide bridges of F(ab').sub.2 fragments. Alternatively, fragments can be prepared via recombinant technology by expressing the heavy and light chain fragments in suitable host cells (e.g., E. coli, yeast, mammalian, plant or insect cells) and having them assembled to form the desired antigen-binding fragments either in vivo or in vitro. A single-chain antibody can be prepared via recombinant technology by linking a nucleotide sequence coding for a heavy chain variable region and a nucleotide sequence coding for a light chain variable region. For example, a flexible linker may be incorporated between the two variable regions. The skilled person is aware of methods for the preparation of both full-length antibodies and antigen binding fragments thereof.

[0165] Thus, in one embodiment there is provided a fusion protein or conjugate as defined herein, wherein said at least one antibody or antigen binding fragment thereof is selected from the group consisting of full-length antibodies, Fab fragments, Fab' fragments, F(ab').sub.2 fragments, Fc fragments, Fv fragments, single chain Fv fragments, (scFv).sub.2 and domain antibodies. In one embodiment, said at least one antibody or antigen binding fragment thereof is selected from full-length antibodies, Fab fragments and scFv fragments. In one particular embodiment, said at least one antibody or antigen binding fragment thereof is a full-length antibody.

[0166] In one embodiment, the antibody or antigen binding fragment thereof is selected from the group consisting of monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, and antigen-binding fragments thereof.

[0167] The term "monoclonal antibodies" as used herein refers to antibodies having monovalent affinity, meaning that each antibody molecule in a sample of the monoclonal antibody binds to the same epitope on the antigen, whereas the term "polyclonal antibodies" as used herein refers to a collection of antibodies that react against a specific antigen, but in which collection there may be different antibody molecules for example identifying different epitopes on the antigen. Polyclonal antibodies are typically produced by inoculation of a suitable mammal and are purified from the mammal's serum. Monoclonal antibodies are made by identical immune cells that are clones of a unique parent cell (for example a hybridoma cell line). The term "human antibody" as used herein refers to antibodies having variable and constant regions corresponding substantially to, or derived from, antibodies obtained from human subjects. The term "chimeric antibodies" as used herein, refers to recombinant or genetically engineered antibodies, such as for example mouse monoclonal antibodies, which contain polypeptides or domains from a different species, for example human, introduced to reduce the antibodies' immunogenicity. The term "humanized antibodies" refers to antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans, in order to reduce immunogenicity.

[0168] In one embodiment, there is provided a fusion protein or a conjugate as disclosed herein, wherein antibody or antigen binding fragment thereof has affinity for a target selected from the group consisting of Tau, apolipoprotein E (ApoE), beta-secretase 1 (BACE1; Atwal et al (2011), Sci Transl Med 3:84ra43), gamma-secretase, transferrin receptor (TfR; Yu et al, (2014) Sci Transl Med 6:261ra154), complement factor C1s, presenilin 1, presenilin 2, nicastrin, alpha-synuclein and Bri.

[0169] The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system (CNS). The BBB is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system and one of its important functions is to block circulating substances from entering or exiting the CNS, which makes drug delivery to the brain challenging. It may therefore be beneficial to target the fusion protein or conjugate to the brain by fusion to a second part which promotes the transport across the BBB. The major mechanisms for delivery of substances into the CNS are transmembrane diffusion and saturable transport. Most CNS therapeutics are small, lipid soluble molecules that are likely to rely upon transmembrane diffusion to cross the BBB. Although peptides, and even some small proteins, have a measurable transmembrane diffusion, saturable transporters are believed to be the most effective mechanism for delivering these molecules into the CNS. Saturable transporters typically deliver 10 to 100 times more of their main ligand to the CNS than would occur with transmembrane diffusion. It may also be of interest to adapt the fusion protein or conjugate such that it can exit the CNS after having bound to the A.beta. target, so that it may for example remove or sequester A.beta. peptide more efficiently.

[0170] Thus, in one embodiment, there is provided a fusion protein or conjugate as disclosed herein, wherein the second part mediates transport of the fusion protein or conjugate to the cerebrospinal fluid and/or brain. In one embodiment, said second part is selected from the group consisting of transferrin, ghrelin, insulin and leptin; for example selected from transferrin and ghrelin.

[0171] In another embodiment, there is provided a fusion protein or conjugate as disclosed, wherein the second part mediates transport away from the cerebrospinal fluid and/or brain. In one such embodiment, said second part is selected from the group consisting of anti-FcRn antibodies (Roopenian and Akilesh (2007), supra) and FcRn-binding Z variants (Seijsing et al (2014), supra) as disclosed in the context of half-life extension above.

[0172] The disclosure furthermore encompasses polypeptides in which the A.beta. peptide binding polypeptide according to the first aspect and as comprised in a fusion protein or conjugate according to the second aspect further comprises a label, such as a label selected from the group consisting of fluorescent dyes and metals, chromophoric dyes, chemiluminescent compounds and bioluminescent proteins, enzymes, radionuclides and radioactive particles. In other embodiments, the labeled A.beta. peptide binding polypeptide is present as a moiety in a fusion protein or conjugate also comprising a second and optionally further parts having a desired biological activity. The label may in some instances be coupled only to the A.beta. peptide binding polypeptide, and in some instances both to the A.beta. peptide binding polypeptide and to the second part of the fusion protein or conjugate. Furthermore, it is also possible that the label may be coupled to a second part, and not to the A.beta. peptide binding part. Hence, in yet another embodiment, there is provided a A.beta. peptide binding polypeptide comprising a second part, wherein said label is coupled to the second part only. Such labels may for example be used for detection of the polypeptide in vivo or in vitro and be useful in diagnosis and therapy monitoring. The skilled person is aware of radionuclides which may be useful in for example positron emission tomography to detect A.beta. and plaques thereof.

[0173] In one embodiment, said A.beta. peptide binding polypeptide, fusion protein or conjugate as described herein comprises a chelating environment provided by a polyaminopolycarboxylate chelator conjugated to the A.beta. peptide binding polypeptide via a thiol group of a cysteine residue or an amine group of a lysine residue.

[0174] In embodiments where the A.beta. peptide binding polypeptide, fusion protein or conjugate is radiolabeled, such a radiolabeled polypeptide may comprise a radionuclide. A majority of radionuclides have a metallic nature and metals are typically incapable of forming stable covalent bonds with elements presented in proteins and peptides. For this reason, labeling of proteins and peptides with radioactive metals is performed with the use of chelators, i.e. multidentate ligands, which form non-covalent compounds, called chelates, with the metal ions. In an embodiment of the A.beta. peptide binding polypeptide, fusion protein or conjugate, the incorporation of a radionuclide is enabled through the provision of a chelating environment, through which the radionuclide may be coordinated, chelated or complexed to the polypeptide.

[0175] One example of a chelator is the polyaminopolycarboxylate type of chelator. Two classes of such polyaminopolycarboxylate chelators can be distinguished: macrocyclic and acyclic chelators.

[0176] In one embodiment, the A.beta. peptide binding polypeptide, fusion protein or conjugate comprises a chelating environment provided by a polyaminopolycarboxylate chelator conjugated to the A.beta. peptide binding polypeptide via a thiol group of a cysteine residue or an epsilon amine group of a lysine residue.

[0177] The most commonly used macrocyclic chelators for radioisotopes of indium, gallium, yttrium, bismuth, radioactinides and radiolanthanides are different derivatives of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). In one embodiment, a chelating environment of the A.beta. peptide binding polypeptide, fusion protein or conjugate is provided by DOTA or a derivative thereof. More specifically, in one embodiment, the chelating polypeptides encompassed by the present disclosure are obtained by reacting the DOTA derivative 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide (maleimidomonoamide-DOTA) with said polypeptide.

[0178] Additionally, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and derivatives thereof may be used as chelators. Hence, in one embodiment, there is provided an A.beta. binding polypeptide, fusion protein or conjugate, wherein the polyaminopolycarboxylate chelator is 1,4,7-triazacyclononane-1,4,7-triacetic acid or a derivative thereof.

[0179] The most commonly used acyclic polyaminopolycarboxylate chelators are different derivatives of DTPA (diethylenetriamine-pentaacetic acid). Hence, polypeptides having a chelating environment provided by diethylenetriaminepentaacetic acid or derivatives thereof are also encompassed by the present disclosure.

[0180] In a third aspect of the present disclosure, there is provided a polynucleotide encoding an A.beta. peptide binding polypeptide or a fusion protein as described herein; an expression vector comprising said polynucleotide; and a host cell comprising said expression vector.

[0181] Also encompassed by this disclosure is a method of producing a polypeptide or fusion protein as described above, comprising culturing said host cell under conditions permissive of expression of said polypeptide from its expression vector, and isolating the polypeptide.

[0182] The A.beta. peptide binding polypeptide of the present disclosure may alternatively be produced by non-biological peptide synthesis using amino acids and/or amino acid derivatives having protected reactive side-chains, the non-biological peptide synthesis comprising [0183] step-wise coupling of the amino acids and/or the amino acid derivatives to form a polypeptide according to the first aspect having protected reactive side-chains, [0184] removal of the protecting groups from the reactive side-chains of the polypeptide, and [0185] folding of the polypeptide in aqueous solution.

[0186] In another aspect, there is provided a composition comprising an A.beta. peptide binding polypeptide, fusion protein or conjugate as described herein and at least one pharmaceutically acceptable excipient or carrier. In one embodiment, said composition further comprises at least one additional active agent, such as at least two additional active agents, such as at least three additional active agents. Non-limiting examples of additional active agents that may prove useful in such a composition are agents selected from the group consisting of inhibitors of neurotransmitter degradation, neurotransmitters, acetylcholinesterase inhibitors, NMDA receptor antagonists, TNF inhibitors, antihistamines, anti-viral agents, alpha-secretase activators, inhibitors of beta- or gamma-secretase, inhibitors of .alpha.-synuclein aggregation, inhibitors of tau aggregation, calcium channel blockers, compounds effective against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair such as pirenzepin and metabolites, attractants for A.beta. clearing/depleting cellular components, inhibitors of N-terminal truncated A.beta. including pyroglutamated A.beta..sub.3-42, anti-inflammatory molecules, atypical antipsychotics such as clozapine, ziprasidone, risperidone, aripiprazole and olanzapine, cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil and galantamine, M1 agonists and other drugs including any amyloid or tau modifying drug and nutritive supplements such as vitamin B12, cysteine, acetylcholine precursor, lecithin, choline, Ginkgo biloba, acetyl-L-carnitine, idebenone, propentofylline, and xanthine derivatives. In one embodiment, the additional active agent(s) is/are selected from the group consisting of acetylcholinesterase inhibitors, NMDA receptor antagonists, TNF inhibitors, antihistamines and anti-viral agents.

[0187] The skilled person will appreciate that said A.beta. peptide binding polypeptide, fusion protein or conjugate, or a composition comprising an A.beta. peptide binding polypeptide, fusion protein or conjugate as described herein may be administered to a subject using standard administration techniques, such as including oral, intravenous, intraperitoneal, subcutaneous, intrathecal (e.g. via the Ommaya reservoir), pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual or suppository administration. Thus, in one embodiment, there is provided a composition or an A.beta. peptide binding polypeptide, fusion protein, conjugate as disclosed herein for administration via a route selected from the group consisting of oral, intravenous, intraperitoneal, subcutaneous, intrathecal, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual or suppository administration, such as selected from the group consisting of oral, intrathecal, intravenous and intranasal administration, in particular intranasal administration.

[0188] A.beta. peptide may also serve as a marker for diagnosis and prognosis of A.beta. peptide associated disorders, such as amyloidosis, which refers to a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders or conditions characterized by a loss of cognitive memory capacity such as, for example, Alzheimer's disease (AD), mild cognitive impairment (MCI), Lewybody dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), the Guam Parkinson-dementia complex; as well as other diseases which are based on or associated with amyloid-like proteins such as cerebral amyloid angiopathy, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), inclusion-body myositis (IBM), type II diabetes, and senile cardiac amyloidosis; and various eye diseases including glaucoma, macular degeneration, drusen-related optic neuropathy, and cataract due to beta-amyloid deposition.

[0189] The A.beta. peptide binding polypeptide according to the present disclosure may be useful as a therapeutic, diagnostic or prognostic agent. Hence, in another aspect of the present disclosure, there is provided an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein for use as a medicament, a diagnostic agent or a prognostic agent.

[0190] It is envisioned that the administration of an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein to a subject afflicted with a disease characterized by an over-representation of A.beta., or by A.beta. aggregates or A.beta. deposits, would likely lower the A.beta. toxicity and promote A.beta. degradation in the subject (Luheshi et al (2010) PLOS Biology, March, Vol 8, Issue 3, e1000334). This, in turn, would also reduce the amount of insoluble A.beta. in the body, because of the shift in equilibrium between soluble and aggregated forms of the amyloid beta peptide. Lowering the amounts of, and/or sequestering, A.beta. in this fashion serves to reduce, and perhaps eliminate, the very source of the disease itself.

[0191] Thus, in one embodiment, there is provided an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein, for use as a medicament to reduce the amount of free A.beta. peptide in blood. In one embodiment, there is provided an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein, for use as a medicament to slow down, stop or reverse the A.beta. monomer-aggregate equilibrium. In one embodiment, there is provided an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein, for use as a medicament to prevent or reverse A.beta. aggregate formation. The skilled person will appreciate that the three above mentioned modes of function of an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as disclosed herein, are not mutually exclusive. Instead, an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as disclosed herein may exert any one, two or all three effects at the same time, or at different time points, for example depending on the effective concentration of said A.beta. peptide binding polypeptide, fusion protein, conjugate or composition in the patient treated as well as on the stage of the disease.

[0192] In one embodiment, there is provided an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition for use in the treatment, diagnosis or prognosis of a A.beta. peptide associated condition selected from the group consisting of amyloidosis, which refers to a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders or conditions characterized by a loss of cognitive memory capacity such as, for example, Alzheimer's disease (AD), mild cognitive impairment (MCI), Lewybody dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), the Guam Parkinson-dementia complex; as well as other diseases which are based on or associated with amyloid-like proteins such as cerebral amyloid angiopathy, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), inclusion-body myositis (IBM), type II diabetes, and senile cardiac amyloidosis; and various eye diseases including glaucoma, macular degeneration, drusen-related optic neuropathy, and cataract due to beta-amyloid deposition. In one embodiment, the A.beta. peptide associated condition is selected from the group consisting of dementia, cognitive impairment, Alzheimer's disease, cerebral amyloid angiopathy, Down's syndrome, type II diabetes, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, glaucoma and age-related macular degeneration. In one particular embodiment, said condition is Alzheimer's disease.

[0193] In a related aspect, there is provided a method of detecting A.beta. peptide, comprising providing a sample suspected to contain A.beta. peptide, contacting said sample with an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein, and detecting the binding of the A.beta. peptide binding polypeptide, fusion protein, conjugate or composition to indicate the presence of A.beta. peptide in the sample. In one embodiment, said method further comprises an intermediate washing step for removing non-bound polypeptide, fusion protein, conjugate or composition, after contacting the sample.

[0194] In one embodiment, said method is a diagnostic or prognostic method, for determining the presence of A.beta. peptide in a subject, the method comprising the steps: [0195] contacting the subject, or a sample isolated from the subject, with an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein, and [0196] obtaining a value corresponding to the amount of the A.beta. peptide binding polypeptide, fusion protein, conjugate or composition that has bound in said subject or to said sample.

[0197] In one embodiment, said method further comprises an intermediate washing step for removing non-bound polypeptide, fusion protein, conjugate or composition, after contacting the subject or sample and before obtaining a value.

[0198] In one embodiment, said method further comprises a step of comparing said value to a reference. Said reference may be scored by a numerical value, a threshold or a visual indicator, for example based on a color reaction. The skilled person will appreciate that different ways of comparison to a reference are known in the art and may be suitable for use.

[0199] In one embodiment of such a method, said subject is a mammalian subject, such as a human subject.

[0200] In one embodiment of such a method, said sample is a biological fluid sample, such as sample selected form the group consisting of a whole blood sample, a plasma sample and a serum sample.

[0201] In another embodiment of such a method, said sample is a tissue sample.

[0202] In one embodiment, said method is performed in vivo.

[0203] In one embodiment, said method is performed in vitro.

[0204] In a related aspect, there is provided a method of treatment of an A.beta. peptide associated condition, comprising administering to a subject in need thereof an effective amount of an A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein. In a more specific embodiment of said method, the A.beta. peptide binding polypeptide, fusion protein, conjugate or composition as described herein reduces the amount of free A.beta. peptide in blood; slows down, stops or reverses the A.beta. monomer-aggregate equilibrium; prevents or reverses A.beta. aggregate formation; or a combination thereof.

[0205] In one embodiment, said A.beta. peptide associated condition is selected from the group consisting of amyloidosis, which refers to a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders or conditions characterized by a loss of cognitive memory capacity such as, for example, Alzheimer's disease (AD), mild cognitive impairment (MCI), Lewybody dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), the Guam Parkinson-dementia complex; as well as other diseases which are based on or associated with amyloid-like proteins such as cerebral amyloid angiopathy, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), inclusion-body myositis (IBM), type II diabetes, and senile cardiac amyloidosis; and various eye diseases including glaucoma, macular degeneration, drusen-related optic neuropathy, and cataract due to beta-amyloid deposition. In one embodiment, the A.beta. peptide associated condition is selected from the group consisting of dementia, cognitive impairment, Alzheimer's disease, cerebral amyloid angiopathy, Down's syndrome, type II diabetes, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, glaucoma and age-related macular degeneration. In one particular embodiment of said aspect, the A.beta. peptide associated condition is Alzheimer's disease.

[0206] It may be beneficial to administer a therapeutically effective amount of an A.beta. peptide polypeptide, fusion protein, conjugate or composition as described herein and at least one second drug substance, such as an agent selected from the group consisting of inhibitors of neurotransmitter degradation, neurotransmitters, acetylcholinesterase inhibitors, NMDA receptor antagonists, TNF inhibitors, antihistamines, anti-viral agents, alpha-secretase activators, inhibitors of beta- or gamma-secretase, inhibitors of .alpha.-synuclein aggregation, inhibitors of tau aggregation, calcium channel blockers, compounds effective against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair such as pirenzepin and metabolites, attractants for A.beta. clearing/depleting cellular components, inhibitors of N-terminal truncated A.beta. including pyroglutamated A.beta..sub.3-42, anti-inflammatory molecules, atypical antipsychotics such as clozapine, ziprasidone, risperidone, aripiprazole and olanzapine, cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil and galantamine, M1 agonists and other drugs including any amyloid or tau modifying drug and nutritive supplements such as vitamin B12, cysteine, acetylcholine precursor, lecithin, choline, Ginkgo biloba, acetyl-L-carnitine, idebenone, propentofylline, and xanthine derivatives. In one embodiment, the at least one second drug substance is selected from the group consisting of acetylcholinesterase inhibitors, NMDA receptor antagonists, TNF inhibitors, antihistamines and anti-viral agents.

[0207] As used herein, the term "co-administration" encompasses concomitant administration and administration in sequence. Thus, in one embodiment there is provided a method as defined above further comprising co-administration of at least one of the agents described above.

[0208] According to another aspect of the present invention, a method of separation, removal and/or purification of the A.beta. peptide is provided. Suitably, such method involves a separation device, such as chosen among chromatographic media, membranes, cellulose, silica, agarose, polyacrylamide, magnetic beads, two-phase systems and other such materials commonly used in separation. In an embodiment, A.beta. peptide binding polypeptide, fusion protein or conjugate as described herein is coupled to the separation device. The thus obtained separation device, having said A.beta. peptide binding polypeptide, fusion protein or conjugate coupled thereto, is referred to as an affinity matrix. Thus, in one aspect of the present disclosure, there is provided an affinity matrix comprising A.beta. peptide binding polypeptide, fusion protein or conjugate as described herein.

[0209] The method comprises a step of affinity separation, in which step an affinity matrix comprising an A.beta. peptide binding polypeptide, fusion protein or conjugate as described herein is used.

[0210] For the purposes of purification of A.beta. peptide from a sample, the sample containing A.beta. to be purified is suitably applied to such an affinity matrix under conditions permissive for binding of A.beta. peptide to the matrix. Thereafter, the affinity matrix is washed under conditions such that the binding of the A.beta. peptide to the matrix is maintained, but most, ideally all, other proteins and contaminants bound to the matrix are washed away. In an elution step, the matrix is treated such that A.beta. peptide is released from the matrix in an A.beta. peptide enriched fraction denoted "A.beta. peptide fraction", which may be recovered.

[0211] If, conversely, the purpose of the separation is the removal of A.beta. peptide, essentially the same steps as above are suitably followed, with some exceptions. The sample containing A.beta. peptide to be removed is suitably applied to an affinity matrix under conditions that are permissive for binding of A.beta. peptide to the matrix. Thereafter, the affinity matrix is washed under conditions such that the binding of A.beta. peptide to the matrix is maintained, but most, ideally all, other proteins are recovered in the flow-through, thus obtaining a "depleted fraction" with a substantial reduction in A.beta. peptide content, which is recovered. The non-A.beta. constituents of the sample may be retained and used and/or processed further.

[0212] Another related aspect of the disclosure is a method for reducing the content of A.beta. peptide in a portion of a body fluid of a human, comprising the steps:

[0213] a) providing a portion of a body fluid from a human;

[0214] b) applying the portion to an affinity matrix as described herein, under conditions permissive for binding of the A.beta. peptide to said affinity matrix, thereby causing a reduction of the content of A.beta. peptide in the portion of body fluid; and

[0215] c) returning at least a part of said portion of body fluid to said human.

[0216] The method according to the disclosure may be directed to reducing the content of A.beta. peptide in a body fluid of a subject afflicted by an A.beta. peptide associated condition selected from the group consisting of dementia, cognitive impairment, Alzheimer's disease, cerebral amyloid angiopathy, Down's syndrome, type II diabetes, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, glaucoma and age-related macular degeneration, such as Alzheimer's disease. The body fluid may for example be whole blood, plasma or serum. Thus, by using the method according to the invention, subjects afflicted by said A.beta. peptide associated condition could be treated by extracorporeal removal of A.beta..

[0217] While the invention has been described with reference to various exemplary aspects and embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or molecule to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to any particular embodiment contemplated, but that the invention will include all embodiments falling within the scope of the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

[0218] FIG. 1 is a listing of the amino acid sequences of examples of A.beta. peptide binding polypeptides of the present disclosure (SEQ ID NO:1-106, 115 and 118-553), the albumin binding domain PP013 (SEQ ID NO:107); a control polypeptide with affinity for an irrelevant target (Z.sub.Taq; SEQ ID NO:108); human A.beta..sub.1-42 peptide (SEQ ID NO:109); human A.beta..sub.1-40 peptide (SEQ ID NO:110); and amino acid sequences for control peptides Z.sub.A.beta.3 (SEQ ID NO:111), (Z.sub.A.beta.3).sub.2 (SEQ ID NO:112), (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113), albumin binding polypeptide ABP (SEQ ID NO:114), (Z.sub.Taq).sub.2-PP013 (SEQ ID NO:116) and the albumin binding domain GA3 from streptococcal Protein G, "ABD" (SEQ ID NO:117) used in selection, screening and/or characterization of the binding polypeptides of the disclosure. The deduced A.beta. peptide binding motifs BM1 and BM2 of the A.beta. peptide binding polypeptides disclosed herein extend from residue 4 to residue 25 and from residue 64 to residue 85, respectively, in the sequences with SEQ ID NO:1-17, 19-106 and 118-553. In SEQ ID NO:18, BM1 and BM2 extend from residue 4 to residue 25 and from residue 69 to residue 90, respectively.

[0219] FIG. 2 is a structural overview of the design of the truncated head-to-tail linked dimeric asymmetric library (A), denoted ZASlib, and symmetric library Z (B), denoted ZSYMlib, shown in complex with the A.beta..sub.1-40 peptide (white mesh ribbon) (Protein Data Bank entry 2OTK). Randomized positions in respective library are indicated, with numbering referring to the respective position in a full-length Z variant.

[0220] FIG. 3 is a schematic comparison between a head-to-tail dimer of the first-generation A.beta. peptide Z.sub.A.beta.3, herein denoted (Z.sub.A.beta.3).sub.2 (SEQ ID NO:112) and the two affinity maturation libraries (A) ZASlib and (B) ZSYMlib. Amino acid sequence positions that are randomized in the libraries are indicated by X and the allowed amino acids in these positions for each library are indicated.

[0221] FIG. 4 are scatter plots showing the results of flow-cytometric sorting of (A) ZASlib and (B) ZSYMlib. Fluorescence intensity on the X axes corresponds to the surface expression level monitored via HSA binding to the albumin binding polypeptide ABP (SEQ ID NO:114) expressed as an integral part of the surface-exposed proteins. Fluorescence intensity on the Y axes corresponds to A.beta. binding. The scatter plots show the staphylococcal library before flow-cytometric sorting in cycles 1, 2, 3 and 4, respectively, with regions used for gating outlined in each plot. Note that the concentration of biotinylated A.beta. peptide is decreased in each sorting cycle and that off-rate selection was performed in the last cycle, resulting in decreasing signal intensities on average in subsequent rounds.

[0222] FIGS. 5A and 5B show the amino acid sequences of (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113) together with the affinity matured A.beta. peptide binding polypeptides isolated by FACS from the asymmetric library (ABPP001, 005, 009, 013, 014, 016, 018, 020, 021, 025, 026, 028, 033, 035, 037, 040, 042, 048, 049 and 050, corresponding to SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49 and 50, respectively) and from the symmetric library (ABPP053, 054, 059, 060, 061, 062, 070, 075, 078, 084, 089, 090, 095, 096, 097, 100 and 104, corresponding to SEQ ID NO:53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104, respectively). The (S.sub.4G).sub.2 linker is outlined between the first and second moieties. Randomized positions are indicated by dots and positions that have been mutated in the original scaffold are shown. The number of times each clone was isolated is shown to the right of each sequence.

[0223] FIG. 6 shows bar graphs of the results from flow-cytometric analysis of on-cell off-rate ranking of (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113) and 37 of the unique affinity matured A.beta. peptide binding polypeptides isolated by FACS (ABPP001, 005, 009, 013, 014, 016, 018, 020, 021, 025, 026, 028, 033, 035, 037, 040, 042, 048, 049, 050, 053, 054, 059, 060, 061, 062, 070, 075, 078, 084, 089, 090, 095, 096, 097, 100 and 104). The A.beta. peptide binding polypeptide variants are represented on the X axis, and the ratio between the mean fluorescence intensity (MFI) corresponding to A.beta. peptide binding and MFI corresponding to surface expression level is represented on the Y axis. The arrowheads indicate the eight clones selected for further characterization.

[0224] FIG. 7 shows an SDS-PAGE gel of cell lysates after SEC purification of the eight selected A.beta. peptide binding polypeptides (ABPP070, 084 and 095 corresponding to SEQ ID NO:70, 84 and 95, respectively, as well as ABPP018, 028, 035, 049 and 050 corresponding to SEQ ID NO:18, 28, 35, 49 and 50, respectively) as well as of (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113). All purified A.beta. peptide binding polypeptides showed a correct size of approximately 14 kDa as estimated from the gel. M indicates lanes with the size marker.

[0225] FIG. 8 shows a sensorgram obtained from affinity measurements of ABPP095 (SEQ ID NO:95) to biotinylated A.beta..sub.1-40 on a neutravidin sensor chip using surface plasmon resonance (SPR) analysis.

[0226] FIG. 9 shows circular dichroism (CD) spectra of ABPP095 (SEQ ID NO:95). FIG. 9A shows a graph of a variable temperature measurement (VTM) spectrum obtained at 221 nm while heating ABPP095 from 20 to 90.degree. C. FIG. 9B shows CD spectra of ABPP095 at wavelengths ranging from 195 to 250 nm at 20.degree. C., before and after variable temperature measurement (VTM).

[0227] FIG. 10 shows the results from SDS-PAGE analysis of protein fractions from ABPP095-PP013 (SEQ ID NO:115) mediated capture of A.beta. peptide from PBS spiked with 50 pg/ml A.beta..sub.1-42. The gel was silver stained for visualization of protein bands. Lane M, molecular weight marker; lane 1, eluate from [HSA Sepharose/ABPP095-PP013] incubated with A.beta..sub.1-42 peptide; lane 2, reference ABPP095-PP013; lane 3, reference A.beta..sub.1-42 peptide.

[0228] FIGS. 11A and 11B show the results from the SDS-PAGE analysis of purified ABPP095-PP013 (SEQ ID NO:115) and (Z.sub.Taq).sub.2-PP013 (SEQ ID NO:116), respectively. FIG. 11A: lane 1, molecular marker; lane 2, 20 .mu.g reduced ABPP095-PP013 protein; lane 3, 20 .mu.g non-reduced ABPP095-PP013 protein. FIG. 11B: lane 1, molecular marker; lane 2, 10 .mu.g reduced (Z.sub.Taq).sub.2-PP013 protein.

[0229] FIG. 12 shows results from the behavioral tests described in Example 8. FIG. 12A shows bar graphs of maximum velocity (Vmax), average velocity (Vmean), distance travelled and resting time obtained from 10 (2.times.Tg) sweAPP/PS1 mice treated with ABPP095-PP013 (SEQ ID NO:115) and 10 (2.times.Tg) sweAPP/PS1 mice treated with (Z.sub.Taq).sub.2-PP013 (SEQ ID NO:116; control) as measured by the locomotor activity test. FIG. 12B shows bargraphs of running speed obtained from 10 (2.times.Tg) sweAPP/PS1 mice treated with ABPP095-PP013 and 10 (2.times.Tg) sweAPP/PS1 mice treated with (Z.sub.Taq).sub.2-PP013 measured by the rotarod test.

[0230] FIG. 13 shows the results from the radial arm maze test obtained from 10 (2.times.Tg) sweAPP/PS1 mice treated with ABPP095-PP013, 10 (2.times.Tg) sweAPP/PS1 mice treated with (Z.sub.Taq).sub.2-PP013 (control) and 10 wild type control mice. The number of errors is shown on the y-axis and the day of testing on the x-axis.

[0231] FIG. 14 shows accumulation of amyloid plaques in motor cortex of (2.times.Tg) sweAPP/PS1 mice. FIGS. 14A and 14B show representative A.beta.-immunostained (6E10/4G8) brain sections from mice treated with (Z.sub.Taq).sub.2-PP013 (control) and ABPP095-PP013, respectively. FIG. 14 C shows bar graphs of the histological quantification of cortical amyloid plaque burden in ABPP095-PP013 treated mice and control-treated mice.

[0232] FIG. 15 shows accumulation of amyloid plaques in dentate gyrus of the hippocampus of (2.times.Tg) sweAPP/PS1 mice. FIGS. 15A and 15B show representative A.beta.-immunostained (6E10/4G8) brain sections from mice treated with (Z.sub.Taq).sub.2-PP013 (control) and ABPP095-PP013, respectively.

[0233] FIG. 15 C shows bar graphs of the histological quantification of hippocampal amyloid plaque burden in ABPP095-PP013 treated mice and control-treated mice.

[0234] FIG. 16 shows astrogliosis in the hippocampus of (2.times.Tg) sweAPP/PS1 mice. FIGS. 16A and 16B show representative GFAP-immunostained brain sections from mice treated with (Z.sub.Taq).sub.2-PP013 (control) and ABPP095-PP013, respectively. FIG. 16 C shows bar graphs of the semi-quantitative analysis of astrocytes in ABPP095-PP013 treated mice as compared to control-treated mice.

[0235] FIG. 17 shows a diffusion time analysis by fluorescence correlation spectroscopy. The diffusion time (.tau..sub.D), reflecting the size of the analyzed component, is presented over time for Alexa467-labeled A.beta..sub.1-40 peptide in the absence (black dots) and presence (grey rings) of ABPP095.

EXAMPLES

Summary

[0236] The following Examples disclose the development of novel A.beta. peptide binding polypeptides based on staphylococcal display technology. The genes encoding the A.beta. peptide binding polypeptides described herein were sequenced, and the corresponding amino acid sequences are listed in FIG. 1 and denoted by the identifiers SEQ ID NO:1-106 and 118-553. The Examples also describe the generation, characterization and functionality of the A.beta. peptide binding polypeptides.

[0237] To clarify, the term "Z variant", as used herein, denotes target binding polypeptides derived from protein Z. Thus, the A.beta. peptide binding polypeptides as described herein comprise dimers of a first Z variant unit and a second Z variant unit, wherein said units may be Z variants which are truncated at the N-terminal end.

Example 1

Design and Cloning of Affinity Maturation Libraries

Summary

[0238] This Example describes the design and cloning of two affinity maturation libraries, ZASlib and ZSYMlib, based on dimers of the previously identified first generation A.beta. peptide binding polypeptide variant Z.sub.A.beta.3 (SEQ ID NO:111).

Materials and Methods

[0239] Two SlonoMax.RTM. head-to-tail dimer libraries of double-stranded DNA were purchased from Sloning BioTechnology GmbH (Pucheim, Germany). Library oligonucleotides encoded the truncated helix 1 plus helix 2 and 3 of the first Z variant unit and helix 1 and 2 of the second Z variant unit, making up the first and second moieties of the A.beta. peptide binding polypeptides (asymmetric library: 5'-GCG GGT GGG GAG NNN NNN TAT NNN NNN AAC TTA AAC GCG NNN CAA CTG TGT GCC TTC ATC NNN AGT TTA GAA GAT GAO CCA AGC CAA NNN GCT AAC TTG TTG GCA GAA GCT AAA AAG CTA AAT GAT GCT CAG GCG CCG GCG AGC AGC AGC AGC GGG AGC AGC AGC AGC GGG CGC GCG AGT GCG GGT CGC GAG NNN GTT TAT TTA NNN AAC TTA AAC GCG NNN CAA CTG TGT GCC NNN ATC NNN AGT NNN GAA GAT GAO NNN AGC CAA NNN GCT AAC TT-3' (SEQ ID NO:556; randomized codons denoted NNN); symmetric library: 5'-GCG GGT NNN GAG NNN GTT TAT NNN NNN AAC TTA AAC GCG NNN CAA CTG TGT GCC TTC ATC NNN AGT TTA GAA GAT GAO NNN AGC CAA NNN GCT AAC TTG TTG GCA GAA GCT AAA AAG CTA AAT GAT GCT CAG GCG CCG GCG AGC AGC AGC AGC GGG AGC AGC AGC AGC GGG CGC GCG AGT GCG GGT NNN GAG NNN GTT TAT NNN NNN AAC TTA AAC GCG NNN CAA CTG TGT GCC TTC ATC NNN AGT TTA GAA GAT GAO NNN AGC CAA NNN GCT AAC TT-3' (SEQ ID NO:557; randomized codons denoted NNN). The genes were flanked with XhoI and NheI restriction sites for subcloning into the staphylococcal vector. The libraries were PCR amplified in 8 cycles using Phusion DNA polymerase (Finnzymes, Espoo, Finland), and the final PCR products were purified using a QIAquick PCR purification kit (Qiagen GmbH). Purified PCR products were digested by XhoI and NheI-HF (New England Biolabs) restriction enzymes and purified by preparative gel electrophoresis (2% agarose gel) using QIAquick gel extraction kit (Qiagen GmbH). The S. carnosus expression vector pSCZ1 (Lofblom et al (2007) J Appl Microbiol 102(3):736-747) was digested by the same enzymes and purified by preparative gel electrophoresis as described above. Purified library fragments were ligated into the vector using T4 DNA ligase (New England Biolabs) at a 1:5 molar ratio of vector to insert, followed by phenol-chloroform extraction and ethanol precipitation for purification and concentration of DNA fragments. Next, the library-encoding plasmids were transformed into electrocompetent E. coli SS320 cells (Lucigen Corporation, Middleton, USA) by electroporation. Individual clones were PCR amplified for subsequent library sequence validation using BigDye Thermo Cycle Sequencing reactions and an ABI Prism 3700 instrument (Applied Biosystems, Foster City, Calif.). Library plasmids were subsequently prepared using a Jetstar Maxi Kit (Genomed), purified by phenol-chloroform extraction and concentrated by isopropanol precipitation. Finally, the libraries (hereafter denoted Sc:ZASlib and Sc:ZSYMlib) were transformed into electrocompetent S. carnosus as previously described (Lofblom et al (2007), supra).

[0240] To verify that the libraries were functionally displayed on the staphylococcal surface, cells were incubated with fluorescently labeled human serum albumin (HSA; Kabi Pharmacia) and analyzed using flow cytometry. Labeling of HSA with Alexa Fluor 647 succinimidyl ester (Invitrogen) was performed according to the supplier's recommendations.

Results

[0241] In order to improve affinity for the A.beta. peptide, an affinity maturation of A.beta. peptide binding polypeptides was performed. Two affinity maturation libraries were designed based on a head-to-tail dimer of the first-generation A.beta. peptide binding polypeptide Z.sub.A.beta.3 (SEQ ID NO:111). The libraries were designed as single-chain dimers to enable independent engineering of respective domain as well as to make them less susceptible to reducing conditions. Previous data show that truncating the first eleven, unstructured, amino acid residues from the N-terminus of a dimer of the first-generation A.beta. peptide binding polypeptide Z.sub.A.beta.3 has positive effects on the affinity for A.beta. peptide (Lindgren et al (2010) Protein Sci 19(12):2319-2329; Lindberg et al (2013) Biotechnol J 8(1):139-145). This portion of the first Z variant unit was therefore excluded in the libraries. In the second Z variant unit, the corresponding portion was instead substituted by a flexible (S.sub.4G).sub.2 linker, in order to allow correct folding of the dimeric construct. The design of the randomizations in both libraries was based on structural analysis of the interaction of the first generation A.beta. peptide binding polypeptide with the A.beta. peptide, and on the sequence output from the selection of first generation A.beta. peptide binding polypeptides (Gronwall et al (2007), supra; Hoyer et al (2008), supra).

[0242] Different approaches were used for randomization of the libraries. In one library, different positions on the two Z variant units were targeted for randomization (asymmetric randomization), whereas in the other library, the same positions in both Z variant units were randomized (symmetric randomization). In the first approach, 15 asymmetrically distributed positions in both Z variant units were partially randomized (library denoted ZASlib; FIG. 2A). In the second approach, 16 symmetrically distributed positions (eight in each Z variant unit) were partially randomized (library denoted ZSYMlib; FIG. 2B). Each randomized position was spiked to 50-75% with the codon for the original amino acid, combined with a mix of codons for 1-4 other amino acids, resulting in a relatively low mutation frequency. To enable the construction of complex randomized DNA oligos, sets of trinucleotide building blocks were combined during production (Slonomics.RTM. technology). This method provided complete freedom when selecting codons for the library and allowed randomizations with minimal biases compared to degenerate codons and error-prone PCR approaches. The designs resulted in theoretical library complexities of 8.1.times.10.sup.7 (ZASlib) and 2.33.times.10.sup.7 (ZSYMlib) individual oligonucleotides. The library designs are outlined in FIG. 3.

[0243] The oligonucleotide mixtures encoding the two libraries were subcloned into the staphylococcal display vector pSCZ1 in fusion to an albumin binding polypeptide (ABP; SEQ ID NO:114) (Lofblom (2007), supra) and transformed into S. carnosus to generate libraries displayed on bacteria, with diversities of approximately 1.times.10.sup.8 (ZASlib) and 1.3.times.10.sup.7 (ZSYMlib). Sequence analysis of individual library members revealed a distribution of codons in accordance with the theoretical design, and no occurrence of undesired codons was observed. However, about 10% of ZSYMlib did not have a complete (S.sub.4G).sub.2 linker. To verify that the libraries were functionally displayed on the staphylococcal surface, cells were incubated with fluorescently labeled HSA and analyzed using flow cytometry. Around 60-67% of the population displayed surface-exposed recombinant proteins, as assessed by functional albumin binding reporter protein. When incubated with labeled A.beta..sub.1-40, both libraries demonstrated a fraction of clones having retained target binding (FIG. 4, cycle 1).

Example 2

Flow Cytometric Sorting of Affinity Maturation Libraries and Sequencing of Isolated Polypeptides

Summary

[0244] This Example describes the cloning of the affinity maturation libraries of Example 1 into a vector for staphylococcal display, and subsequent sorting and selection of A.beta. peptide binding polypeptides by flow cytometry utilizing increased stringency conditions in each sorting cycle. Sequencing of isolated variants lead to the identification of 51 unique variants from the asymmetric library (SEQ ID NO:1-51) and 55 unique variants from the symmetric library (SEQ ID NO:52-106).

Materials and Methods

[0245] At least ten times the library size of either library was inoculated to tryptic soy broth supplemented with yeast extract (TSB+Y; Merck, Darmstadt, Germany) and 20 .mu.g/ml chloramphenicol, and grown overnight at 37.degree. C. and 150 rpm. The following day, cells were harvested by centrifugation (6000 rpm, 6 min, 4.degree. C.) and washed in phosphate-buffered saline supplemented with 0.1% Pluronic.RTM. F108 NF Surfactant (PBSP; pH 7.4; BASF Corporation) before addition of C-terminally biotinylated A.beta..sub.1-40 peptide (SEQ ID NO:110; AnaSpec). Cells were incubated with gentle mixing at room temperature for 45 minutes until equilibrium was reached. Subsequently, cells were washed with ice-cold PBSP and labeled with streptavidin conjugated with phycoerythrin (SAPE; Invitrogen) as well as HSA conjugated with Alexa Fluor 647 for 30 minutes on ice at concentrations of 5 .mu.g/ml and 150 nM, respectively. After a final washing step in ice-cold PBSP, cells were resuspended in ice-cold PBSP prior to sorting. Cells were sorted in four cycles with an increased stringency in each cycle, using a MoFlo.RTM. Astrios flow cytometer (Beckman Coulter). In the first cycle of selection, library cells were incubated with 50 nM C-terminally biotinylated A.beta..sub.1-40 peptide, and with 20 nM and 10 nM, respectively, in the second and third cycles. In the last cycle, the cells were subjected to an off-rate selection procedure.

[0246] In the final, off-rate selection cycle, enriched library cells were incubated with 25 nM C-terminally biotinylated A.beta..sub.1-40 peptide for 45 minutes to reach equilibrium binding, washed in ice-cold PBSP, incubated with 100 nM unlabeled A.beta..sub.1-40 peptide for 6 h and then labeled with HSA-Alexa Fluor 647 and SAPE prior to FACS sorting. In each sorting cycle, approximately ten times the library size was analyzed in the flow cytometer and the top fraction of cells (approximately 0.35%) with the highest ratio of A.beta..sub.1-40-binding to cell surface expression fluorescence was gated and sorted directly into TSB+Y. Sorted cells were inoculated to TSB+Y supplemented with chloramphenicol (10 .mu.g/ml) for overnight amplification at 37.degree. C. with 150 rpm shaking, prior to the next cycle of FACS.

[0247] After the final cycle of sorting, cells were spread onto agar plates containing 10 .mu.g/ml chloramphenicol. 96 randomly picked colonies from each sorted library were sequenced using BigDye Thermo Cycle Sequencing reactions and an ABI Prism 3700 (Applied Biosystems).

Results

[0248] Staphylococcal display technology in combination with fluorescence-activated cell sorting (FACS) is well suited for affinity maturation purposes, since it offers fine affinity discrimination between individual library members (Lofblom (2007) supra; Kronqvist (2008) Protein Eng Des Sel 21(4):247-255; Maim et al (2013) PLoS One 8(5):e62791). In order to isolate high-affinity A.beta. peptide binding polypeptides, the two displayed libraries were subjected to four cycles of FACS. Staphylococcal cells were incubated with biotinylated A.beta..sub.1-40 peptide for 45 min at room temperature to reach binding equilibrium. Cells were thereafter washed and incubated on ice with fluorescently labeled HSA and streptavidin-conjugated phycoerythrin, for detection and normalization of the target binding with cell surface expression level as described previously (Kronqvist et al (2008) supra). After additional washing, library cells demonstrating the highest target-binding to surface-expression ratio in the flow cytometer were gated (as outlined in FIG. 4) and isolated for amplification and subsequent rounds of sorting. In each cycle, the selection stringency was increased by changing sorting parameters and gates, as well as by decreasing the target concentration to 50 nM, 20, nM and 10 nM in cycles 1, 2 and 3, respectively. In the fourth and final cycle, an off-rate selection approach was used to favor binders with the slowest dissociation. As shown by flow-cytometric analysis after each cycle of selection, the sorting resulted in enrichment of A.beta. binding clones (FIGS. 4A and 4B). After four cycles of sorting, individual colonies were sequenced for identification. Out of a total of 192 sequences (96 per library), 51 unique polypeptide variants (SEQ ID NO:1-51) were identified in the output from the asymmetric library and 55 unique polypeptide variants (SEQ ID NO:52-106) were identified in the output from the symmetric library (FIG. 1). Interestingly, one isolated clone (ABPP018, SEQ ID NO:18) from the asymmetric library contained a linker consisting of three S.sub.4G repeats instead of the two that were intended by design.

Example 3

On-Cell Screening for A.beta. Binding

Summary

[0249] In this Example, the affinity of 37 isolated polypeptide variants for A.beta. peptide was analyzed by flow cytometry.

Materials and Methods

[0250] 37 clones (ABPP001, 005, 009, 013, 014, 016, 018, 020, 021, 025, 026, 028, 033, 035, 037, 040, 042, 048, 049 and 050, corresponding to SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49 and 50, respectively; and ABPP053, 054, 059, 060, 061, 062, 070, 075, 078, 084, 089, 090, 095, 096, 097, 100 and 104, corresponding to SEQ ID NO:53, 54, 59, 60, 61, 62, 70, 75, 78, 84, 89, 90, 95, 96, 97, 100 and 104, respectively), each occurring more than once in the selection results of Example 2, were individually inoculated to TSB+Y with chloramphenicol (10 .mu.g/ml) and grown overnight at 37.degree. C. and 150 rpm. 10.sup.6 overnight-cultured cells were pelleted by centrifugation and washed in PBSP before resuspension in 1 nM biotinylated A.beta..sub.1-40 (AnaSpec). After 45 min incubation at room temperature with gentle mixing, cells were washed with ice-cold PBSP and labeled with SAPE and HSA-Alexa Fluor 647 for 30 minutes on ice. Next, cells were washed and resuspended in ice-cold PBSP, and subjected to flow-cytometric analysis. The mean fluorescence intensities (MFI) from A.beta..sub.1-40 binding and cell surface expression were measured in a Gallios flow cytometer (Beckman Coulter). The head-to-tail homodimer of the first-generation binder (Z.sub.A.beta.3).sub.2 (SEQ ID NO:112) as well as the head-to-tail homodimer (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113), in which eleven N-terminal amino acid residues were truncated, were included in the analysis for comparison. The experiment was carried out in duplicates on different days using freshly prepared solutions.

Results

[0251] 37 candidates, isolated from the libraries as described in Example 2, were individually subjected to flow-cytometric analysis to screen for the highest A.beta. binding signals. In total, 19 variants from ZASlib (ABPP001, 005, 009, 013, 014, 016, 020, 021, 025, 026, 028, 033, 035, 037, 040, 042, 048, 049 and 050, respectively) and 17 from ZSYMlib (ABPP053, 054, 059, 060, 061, 062, 070, 075, 078, 084, 089, 090, 095, 096, 097, 100 and 104, respectively), appearing multiple times in the sequence analysis, as well as the variant ABPP018 (SEQ ID NO:18) from the asymmetric library containing a longer linker, were included in the assay. Recombinant bacteria were incubated with 1 nM biotinylated A.beta..sub.1-40 and secondary reagents as described above. The samples were subsequently analyzed for A.beta. peptide binding in a flow cytometer, and the ratio of the signal from A.beta. peptide binding to the signal from surface expression level (FL-2/FL-6) was determined. The head-to-tail homodimer of Z.sub.A.beta.3 with an N-terminal truncation (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113) was included in the analysis for comparison. All variants demonstrated higher binding-signals than the control, indicating an improved affinity for the A.beta. peptide.

Example 4

On-Cell Off-Rate Ranking and Determination of Binding

Summary

[0252] In this Example, the 37 polypeptide variants expressed on the staphylococcal cell surface and studied in Example 3, were ranked based on their affinity for A.beta. peptide as measured by their off-rate.

Materials and Methods

[0253] Individual staphylococcal clones (ABPP001, 005, 009, 013, 014, 016, 018, 020, 021, 025, 026, 028, 033, 035, 037, 040, 042, 048, 049, 050, 053, 054, 059, 060, 061, 062, 070, 075, 078, 084, 089, 090, 095, 096, 097, 100 and 104) were inoculated to TSB+Y with chloramphenicol (10 .mu.g/ml) and grown overnight at 37.degree. C. and 150 rpm. 10.sup.6 cells were cultured overnight, pelleted by centrifugation and washed in PBSP before resuspension in 100 nM unlabeled A.beta..sub.1-40 in PBSP. After 6 h incubation at room temperature with gentle mixing, cells were washed with ice-cold PBSP and incubated with 25 nM C-terminally biotinylated A.beta..sub.1-40 peptide (AnaSpec) in PBSP at room temperature for 45 min. Subsequently, cells were washed with ice-cold PBSP and labeled with SAPE and HSA-Alexa Fluor 647 for 30 minutes on ice. The cells were washed and resuspended in ice-cold PBSP, prior to flow-cytometric analysis. The mean fluorescence intensities (MFI) from A.beta..sub.1-40 binding and cell surface expression were measured in a Gallios flow cytometer (Beckman Coulter). The head-to-tail homodimer (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113) was included in the analysis for comparison. The experiment was carried out in duplicates on different days using freshly prepared solutions.

Results

[0254] In order to limit the number of A.beta. peptide binding variants for further analysis, the 37 unique clones were ranked by off-rate measurements while expressed on the staphylococcal cell surface. After incubation of binding variants with biotinylated A.beta..sub.1-40, unlabeled A.beta. peptide was added in 4-fold excess and dissociation was allowed. Then, the ratio between A.beta. peptide binding and surface expression level was determined (FL-2/FL-6). All clones demonstrated considerably slower dissociation from the A.beta. peptide compared to (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113) (FIG. 6).

[0255] Eight variants were chosen for further study (ABPP070, 084, 095, 018, 028, 035, 049 and 050 corresponding to SEQ ID NO:70, 84, 95, 18, 28, 35, 49 and 50, respectively). Four of these demonstrated the highest A.beta. binding from affinity screening, whereas four others exhibited the best off-rate. The selected clones are indicated by arrows in FIG. 6.

Example 5

Expression and Purification of Soluble A.beta. Peptide Binding Polypeptides

Summary

[0256] In this Example, the eight polypeptides selected in Example 4, i.e. ABPP070, 084, 095, 018, 028, 035, 049 and 050, were expressed and purified by immobilized metal ion affinity chromatography (IMAC).

Materials and Methods

[0257] Eight affinity maturated A.beta. binding polypeptides and (Z.sub.A.beta.3A12).sub.2 (SEQ ID NO:113) were produced and purified for further characterization. The DNA sequences encoding the polypeptides were amplified from colonies by PCR, using primers that introduced an upstream NdeI and downstream XhoI restriction site. The DNA sequences were subsequently subcloned into the NdeI and XhoI digested expression vector pET26b+(Novagen), generating constructs with a C-terminal His.sub.6 tag. The plasmids were transformed into BL21 E. coli cells by heat shock. Cells were cultured in TSB at 37.degree. C. and when OD.sub.600 reached approximately 1, expression was induced by addition of IPTG to a final concentration of 1 mM. After overnight incubation at 25.degree. C., the cells were harvested by centrifugation (4000 rpm, 8 minutes, 4.degree. C.). Cells were then lysed by sonication and cell debris was removed by centrifugation (16,000 rpm, 20 minutes, 4.degree. C.). A.beta. peptide binding polypeptides were purified by IMAC using a HisPur.TM. Cobalt resin (Thermo Scientific) under native conditions (wash buffer: 20 mM NaHPO.sub.4, 300 mM NaCl, 15 mM imidazole, pH 7.4, 0.45 .mu.m filtered; elution buffer: 20 mM NaHPO.sub.4, 300 mM NaCl, 150 mM imidazole, pH 7.4, 0.45 .mu.m filtered). Next, potential multimers were removed by size exclusion chromatography (SEC) on an AKTAexplorer 10 using a Superdex 75 gel filtration column (GE Healthcare) and PBS as running buffer. The molecular weight and purity of the A.beta. peptide binding polypeptides were subsequently verified by LC/MS (Agilent Technologies 6520 ESI-Q-TOF) and SDS-PAGE under both reducing and non-reducing conditions. The protein concentration was determined by absorbance measurement at 280 nm.

Results

[0258] Eight A.beta. peptide binding polypeptides (ABPP070, 084, 095, 018, 028, 035, 049 and 050, corresponding to SEQ ID NO:70, 84, 95, 18, 28, 35, 49 and 50, respectively) from the on-cell ranking were subcloned to an expression vector and produced in E. coli as C-terminally His.sub.6 tagged polypeptides. The polypeptides were purified by IMAC followed by SEC to remove potential multimeric complexes. SDS-PAGE analysis of the eluted fractions under both reducing and oxidizing conditions demonstrated pure proteins having the correct size of approximately 14 kDa (FIG. 7).

Example 6

Characterization of A.beta. Peptide Binding Polypeptides

Summary

[0259] In this Example, the affinity for A.beta. peptide of the polypeptides expressed in Example 5, i.e. ABPP070, 084, 095, 018, 028, 035, 049 and 050, was analyzed using surface plasmon resonance (SPR) and ABPP095 was further characterized by circular dichroism (CD) spectroscopy.

Materials and Methods

[0260] Biosensor analysis of off-rate and affinity: The affinities of the purified A.beta. peptide binding polypeptides were determined using an SPR-based biosensor assay on a ProteOn XPR36 instrument (Bio Rad Laboratories, CA, USA). N-terminally biotinylated A.beta..sub.1-40 peptide (AnaSpec) was injected over a Neutravidin sensor chip (Bio Rad Laboratories) for immobilization (immobilization levels were approximately 50 RU). Duplicate samples of each polypeptide were injected at concentrations ranging from 6.25 nM to 50 nM over immobilized A.beta. peptides. The flow rate was 50 .mu.l/min and the association and dissociation was followed for 300 seconds and 2 hours, respectively. HBS-EP was used as running buffer and 0.5% SDS was used for regeneration. In all experiments, subtraction of responses from each sample over a blank surface was performed to minimize buffer contributions. The on and off rates were determined by non-linear regression to a Langmuir 1:1 model using the Proteon Manager Software (BioRad Laboratories).

[0261] Circular Dichroism Spectroscopy:

[0262] The secondary structure content of the affinity-maturated A.beta. peptide binding polypeptide ABPP095 (SEQ ID NO:95) was analyzed at a concentration of 0.2 mg/ml by CD spectroscopy using a Jasco J-810 spectropolarimeter (Jasco Scandinavia AB, Molndal, Sweden) in a cell with an optical path-length of 1 mm. The thermal stability was measured at 221 nm while heating ABPP095 from 20 to 90.degree. C. (5.degree. C./min). A CD spectrum at 250-195 nm was obtained at 20.degree. C. before and after heating to 90.degree. C.

Results

[0263] Biosensor Analysis of Off-Rate and Affinity:

[0264] The eight purified A.beta. peptide binding polypeptides were subjected to affinity and off-rate determination using an SPR-based biosensor assay (Table 4). A dilution series of four different concentrations of each binder was injected over a Neutravidin chip surface with immobilized biotinylated A.beta. peptides. The rate constants of the interactions were determined for all candidates by non-linear regression using a one-site binding model and then used for calculation of K.sub.D values. ABPP095 demonstrated the highest affinity to A.beta..sub.1-40, exhibiting an approximate dissociation constant K.sub.D of 340 pM, corresponding to a 50-fold improved affinity as compared to the reported 17 nM affinity for the first-generation binder (Hoyer, 2008, supra). Dissociation was followed during 2 h, and the off-rate for ABPP095 was determined to 3.2.times.10.sup.-5 s.sup.-1 (FIG. 8).

TABLE-US-00011 TABLE 4 Mean kinetic data for binding to A.beta. peptide SEQ ID K.sub.D k.sub.a k.sub.d NO: (M, mean .+-. SD).sup.1 (M.sup.-1s.sup.-1, mean .+-. SD).sup.1 (s.sup.-1, mean .+-. SD).sup.1 ABPP070.sup.2 70 5.9 .times. 10.sup.-10 .+-. 0.4 7.2 .times. 10.sup.4 .+-. 0.6 4.2 .times. 10.sup.-5 .+-. 0.05 ABPP084 84 1.4 .times. 10.sup.-9 .+-. 1.4 1.1 .times. 10.sup.5 .+-. 0.9 1.5 .times. 10.sup.-4 .+-. 0.04 ABPP095.sup.2 95 3.4 .times. 10.sup.-10 .+-. 0.0 9.4 .times. 10.sup.4 .+-. 0.2 3.2 .times. 10.sup.-5 .+-. 0.04 ABPP018 18 9.7 .times. 10.sup.-10 .+-. 0.0 9.1 .times. 10.sup.4 .+-. 0.3 8.8 .times. 10.sup.-5 .+-. 0.02 ABPP028 28 1.02 .times. 10.sup.-9 .+-. 0.1 8.8 .times. 10.sup.4 .+-. 0.6 9.0 .times. 10.sup.-5 .+-. 0.04 ABPP035 35 2.6 .times. 10.sup.-9 .+-. 0.9 2.8 .times. 10.sup.4 .+-. 0.9 6.7 .times. 10.sup.-5 .+-. 0.09 ABPP049 49 1.15 .times. 10.sup.-9 .+-. 0.0 1.3 .times. 10.sup.5 .+-. 0.2 1.5 .times. 10.sup.-4 .+-. 0.01 ABPP050 50 6.9 .times. 10.sup.-9 .+-. 6.1 1.6 .times. 10.sup.3 .+-. 1.3 7.1 .times. 10.sup.-5 .+-. 0.40 .sup.1Analyzed in duplicates .sup.27600 seconds' dissociation in biosensor experiments

[0265] Circular Dichroism Spectroscopy:

[0266] To further characterize the A.beta. peptide binding polypeptide with the highest affinity (ABPP095), its thermal stability and secondary structure content was analyzed with circular dichroism spectroscopy. The analysis indicated that the A.beta. peptide binding polypeptide had retained a similar secondary structure as the first-generation binder (Hoyer et al (2008), supra). To determine the thermal stability of the polypeptide, the sample was heated from 20 to 90.degree. C., while monitoring the helical content, resulting in a Tm value of approximately 43.degree. C. (FIG. 9A), which is similar to the original variant Z.sub.A.beta.3 (Hoyer et al (2008), supra). Additionally, a CD spectrum was obtained after the variable temperature measurement in order to assess the reversibility of unfolding after heat treatment. The spectrum revealed a perfect overlap with the spectrum from the unheated sample, suggesting that ABPP095 refolded completely after heating to 90.degree. C. (FIG. 9B).

Example 7

Capture of A.beta. Peptide from Spiked E. coli Lysate

Summary

[0267] In this Example, the ability of ABPP095 (SEQ ID NO:95) to capture A.beta. peptide in a complex solution was studied using affinity analysis.

Materials and Methods

[0268] ABPP095 was genetically fused on the C-terminal via a 10 amino acid flexible linker to a 46 amino acid albumin binding domain denoted PP013 (SEQ ID NO:107). Genes were ligated into a PET based expression vector under the control of the T7 promoter and containing a gene for kanamycin resistance. DNA sequence verification, plasmid preparation and cultivation were done essentially as described above. Protein purification was performed essentially as previously described (Jonsson et al (2008) Prot Eng Des Sel 21(8):515-527), but the affinity chromatography matrix was equipped with an anti-[albumin binding domain] ligand (produced in house) instead of human serum albumin.

[0269] 700 .mu.g of ABPP095-PP013 (SEQ ID NO:115) was non-covalently coupled to 1 ml HSA-Sepharose 4 fast flow (GE Healthcare, Uppsala, Sweden) by batch binding at room temperature for 20 min with gentle mixing. HSA-Sepharose samples with bound polypeptides were then incubated with PBS spiked with 50 pg/ml A.beta..sub.1-42 peptide for 1.5 h with gentle mixing. Sepharose was pelleted by centrifugation and washed with 50 ml PBS prior to elution (0.3 M HAc, pH 2.8) of captured A.beta..sub.1-42 peptide from the HSA-Sepharose. Eluates were lyophilized using SpeedVac (Savant Instruments, Milford, Mass., USA) and dissolved in reducing sample buffer (20 mM Tris-HCl pH 8.0, 1 mM EDTA, 2.5% SDS, 5% .beta.-mercaptoethanol, 0.01% BFB). The samples were heated at 96.degree. C. for 10 min and loaded onto a 12% bis-Tris NuPAGE gel (Invitrogen, Carlsbad, Calif., USA) using MES running buffer (50 mM MES, 50 mM Tris base, 0.1 SDS, 1 mM EDTA, pH 7.3). Molecular weights were estimated using SeaBlue2 Pre-stained marker (Invitrogen). The gel was stained by silver stain (SilverXpress.RTM. Silver Staining Kit, Invitrogen), according to the manufacturer's instructions.

Results

[0270] The ability of ABPP095-PP013 (SEQ ID NO:115) to capture A.beta. peptide was studied using affinity analysis. It is likely that the potency of the A.beta. peptide binding polypeptide would benefit from a long in vivo half-life, and it has previously been demonstrated that fusion of molecules to an albumin binding domain dramatically improves the time in circulation by binding to serum albumin (Andersen et al (2011) J Biol Chem 286(7):5234-5241; Orlova et al (2013) J Nucl Med 54(6):961-968). ABPP095 was therefore fused to PP013, and the assay was designed to assess whether the polypeptide could capture A.beta. while simultaneously interacting with albumin. ABPP095-PP013 was first bound to HSA-Sepharose and then incubated with PBS containing A.beta..sub.1-42 (50 pg/ml). This concentration of A.beta..sub.1-42 peptides was chosen to reflect physiological levels of A.beta..sub.1-42 peptides in the blood, although levels have been reported to vary significantly between patients (Kou et al (2000), supra; Du et al (2005), supra; Pesini et al (2012), supra). SDS-PAGE analysis of the elutate from the capture demonstrated that ABPP095 was capable of efficient and selective capture of A.beta..sub.1-42 peptides (FIG. 10). Higher molecular range bands in the eluate were probably due to unspecific binding of proteins to the HSA-Sepharose. Nevertheless, the unspecific binding did not appear to significantly affect the capacity of the A.beta. peptide binding polypeptide to bind A.beta..

Example 8

Locomotor and Cognitive Testing of Alzheimer's Disease Model Mice Treated with A.beta. Peptide Binding Polypeptides

Summary

[0271] In this Example, the sensorimotor and cognitive abilities of Alzheimer's disease model mice treated with ABPP095 (SEQ ID NO:95) fused to an albumin binding domain is compared to Alzheimer's disease model mice treated with a dimer of the control polypeptide Z.sub.Taq (SEQ ID NO:108) fused to said albumin binding domain.

Materials and Methods

[0272] Protein production: ABPP095-PP013 (SEQ ID NO:115) and (Z.sub.Taq).sub.2-PP013 (SEQ ID NO:116) were prepared as described in Example 7. To remove multimers, additional purification was performed by size exclusion chromatography using a HiLoad 16/60 column in an AKTA system (GE Healthcare) and PBS as running buffer. Potential residual endotoxins were removed by passing proteins through 1 ml EndoTrap columns (Hyglos) according to the supplier's recommendations. The proteins were eluted in DPBS (Gibco, Life Technologies) at a concentration of 1 mg/ml. Molecular weight and purity of the proteins were subsequently verified by LC/MS and SDS-PAGE under both reducing and non-reducing conditions. A large amount of protein (20 .mu.g) in reduced as well as non-reduced form was loaded on the SDS-PAGE gel in order to detect potential multimers. The protein concentration was determined by absorbance measurement at 280 nm.

[0273] Treatment of Transgenic Mice:

[0274] Animal studies were approved by the New York University School of Medicine Institutional Animal Care and Use Committee and were consistent with the recommendations of the American Veterinary Association. To model vascular amyloid deposition and amyloid related pathology, the well-characterized double-transgenic (2.times.Tg) sweAPP/PS1 mouse model was used. The model allows expression of the APPK670N/M671L mutations ("the Swedish mutation") as well as the PS1M146V mutation, and has an early onset of AD pathology. Twenty animals were divided into two groups and received intraperitoneal (i.p.) injections of 100 .mu.g (in a volume of 100 .mu.l) of ABPP095-PP013 protein or the irrelevant (Z.sub.Taq).sub.2-PP013 protein three times per week for 13 weeks, beginning at 3-4 months of age. 10 mice were treated with ABPP095-PP013 protein and 10 mice were treated with the negative control (Z.sub.Taq).sub.2-PP013 protein. During the treatment, veterinary staff monitored animals for any signs of toxicity, such as changes in body weight, physical appearance, and altered behavior. At 6-7 months, the mice went through extensive behavioral testing and were subsequently killed for tissue analyses at 7-8 months of age.

[0275] Behavioral Studies:

[0276] Before cognitive testing, exploratory locomotor activity and accelerating rotarod performance tests were performed, in order to measure motor coordination and balance. This was done in order to exclude that any observed effects in the performance of the cognitive tasks were due to differences in sensorimotor abilities.

[0277] Locomotor Activity:

[0278] A Hamilton-Kinder Smart-frame Photobeam System was used to record activity of the mice over a designated period of time. After habituation in a circular open field chamber (70 cm in diameter) for 15 min, each mouse was allowed to explore the environment for 15 min. Horizontal movements of the mice were automatically recorded by a video camera mounted above the chamber. After each session, the field was cleaned with water and 30% ethanol. Results were reported as distance traveled (cm), average and maximum travel velocity (cm/s) and mean resting time (s) for each animal.

[0279] Rotarod Performance:

[0280] Each animal was placed on a rod apparatus, with a rod diameter of 3.6 cm, to assess differences in motor coordination and balance (Rotarod 7650 accelerating model; Ugo Basile) between mice treated with ABPP095-PP013 protein and mice treated with (Z.sub.Taq).sub.2-PP013 protein. The animals were habituated to the apparatus for two training trials in order to reach a baseline level of performance. The animals were subsequently tested in three additional trials with 15 minute intervening periods. The rotarod was set to an initial speed of 1.0 rpm, which was gradually raised every 30 s by 0.5 rpm. A soft foam cushion was placed under the rod to prevent injury from falling. The rod was cleaned with water and 30% ethanol after each session. To assess the performance, the total time on the rod and the speed of the rod were recorded when the mouse fell or inverted (by clinging) from the top of the rotating barrel.

[0281] Radial Arm Maze:

[0282] Spatial memory was assessed using an eight-arm radial maze with eight 30 cm long arms originating from a central space. 0.25 ml of 0.1% aqueous saccharine solution was placed at the end of each arm. In addition to (2.times.Tg) sweAPP/PS1 mice treated with ABPP095-PP013 and the (2.times.Tg) sweAPP/PS1 mice treated with (Z.sub.Taq).sub.2-PP013, an age-matched control group of wild type mice (n=10) was included in this experiment.

[0283] Before testing, the mice were deprived of water for 24 h and their access to water was restricted to 1-2 h per day for the duration of testing. The animal entered and exited the maze through the central area. Clear Plexiglas guillotine doors, operated by a remote pulley system, controlled access to the arms from the central area. After two days of adaptation to the maze, water restricted mice were given one training session per day for 10-11 consecutive days. Prior to each day's testing, the mice were adapted to the room with the lights on for 15 min. The animals were also adapted to the instrument and permitted to enter all arms until the eight rewards (baits containing saccharine) had been consumed. The number of errors (entry into previously visited arms) was recorded.

[0284] Statistical Analysis:

[0285] Data from the exploratory locomotor activity test, the accelerating rotarod performance test and the radial arm maze test was analyzed using two-way ANOVA, repeated measures and a Neuman Keuls (Statistica) or a Bonferroni (GraphPad, San Diego, Calif.) post hoc test.

Results Protein Production:

[0286] It was expected that the potency of an A.beta. peptide binding polypeptide as a therapeutic agent would benefit from a long in vivo half-life. It has previously been demonstrated that fusing Z variant molecules, with affinities for other, non-related targets, to an affinity-matured albumin binding domain significantly improved the in vivo half life by binding to serum albumin. Therefore, in preparation for in vivo analysis, the high-affinity A.beta.-specific ABPP095 polypeptide and a dimer of the control polypeptide Z.sub.Taq were subcloned and expressed in fusion with a C-terminal deimmunized high-affinity albumin binding domain PP013. A 10 amino acid linker separating the polypeptide and albumin binding domain was used. Z.sub.Taq was cloned as a head-to-tail dimer to mimic the format of ABPP095. Approximately 300 mg of each protein was produced and purified for in vivo studies. Multimers were removed by size exclusion chromatography and potential endotoxins were removed using EndoTrap columns. The molecular weight and purity of the proteins were verified by LC/MS and SDS-PAGE (FIG. 11) and the protein concentration was determined.

[0287] Behavioral Studies:

[0288] Groups of (2.times.Tg) sweAPP/PS1 mice treated with ABPP095-PP013 or with (Z.sub.Taq).sub.2-PP013 (control), were assessed in both cognitive and sensorimotor tests. No significant differences were observed between the groups in locomotor activity in terms of distance traveled, rest time, maximum speed, and mean velocity (FIG. 12A). In correlation with this, no difference was observed in the rotarod performance test between transgenic mice treated with ABPP095-PP013 and transgenic mice with (Z.sub.Taq).sub.2-PP013 (control) (FIG. 12B). Thus, the performance in the cognitive test was not confounded by the differences or abnormalities in motor function.

[0289] In the radial arm maze, (2.times.Tg) sweAPP/PS1 mice treated with ABPP095-PP013, as well as wild type mice used as control, showed a significantly better performance compared to the transgenic mice injected with control polypeptide. No differences in performance were observed between the wild-type controls and the transgenic mice treated with ABPP095-PP013 (FIG. 13). Two-way repeated measures ANOVA revealed a significant cognition improvement benefit of ABPP095-PP013 treatment as compared to injection of (ZTaq).sub.2-PP013. Thus, treatment with ABPP095-PP013 significantly improved the cognitive abilities of the transgenic Alzheimer's disease model mice as evaluated in the radial arm maze.

Example 9

Histologic Analysis of Alzheimer's Disease Model Mice Treated with A.beta. Peptide Binding Polypeptide

Summary

[0290] This Example describes histological analyses of (2.times.Tg) sweAPP/PS1 mice, treated with the A.beta. peptide binding polypeptide ABPP095-PP013 or control polypeptide and sacrificed after the behavioral study described in Example 8. The results demonstrated that ABPP095-PP013 substantially reduced the brain amyloid burden, and that this effect correlated with behavioral amelioration in the treated (2.times.Tg) sweAPP/PS1 mice.

Materials and Methods

[0291] Mice were anesthetized with sodium pentobarbital (150 mg/kg i.p.), perfused transaortically and the brains were immediately removed and processed. The right hemisphere was immersion-fixed overnight in periodate-lysine-paraformaldehyde. Following fixation, the brain was moved to a phosphate buffer solution containing 20% glycerol and 2% dimethylsulfoxide (DMSO) and stored at 4.degree. C. until sectioned. Serial coronal brain sections (40 .mu.m) were cut, placed in ethylene glycol cryoprotectant and stored at -20.degree. C. until used. Sections were stained for immunohistochemical analysis with i) a mixture of the anti-A.beta. monoclonal antibodies 6E10 and 4G8 (Covagen Research Products Inc), ii) polyclonal anti-glial fibrillary acidic protein (GFAP) antibody (DAKO) to detect astrocytes. The staining was performed as previously described (Boutajangout et al (2009) J Alzheimers Dis18:961-72; Scholzova et al (2009) J Neuroscience 29:1846-54; Liu et al (2014) J Neurochem 128:577-91).

[0292] Amyloid burden was quantified by a Bioquant stereology image analysis system (BIOQUANT Image Analysis Corporation) using a random unbiased sampling scheme. Total A.beta. burden (defined as the percentage of test area occupied by A.beta. immunoreactivity) was quantified for the cortex and hippocampus on coronal plane sections stained with a mixture of the anti-A.beta. monoclonal antibodies 6E10 and 4G8.

[0293] The assessment of sections stained with the GFAP antibody was based on a semi-quantitative analysis, using methods previously published (Yang et al (2011) J Alzheimers Dis 24:269-285; Scholtzova et al (2009) supra; Sadowski et al (2006) Proc Natl Acad Sci 103:18787-92). Prior to analysis, brains were observed through the microscope and given a rating from 0-4, in increments of 0.5, depending on the degree of pathology and/or the activation stage of the glial cells. Approximately five cortical sections and six hippocampal sections were analyzed per animal. The rating was based on the number of reactive neuronal bodies and processes. Astrogliosis was analyzed at 10.times. magnifications in the cortex, hippocampus and thalamus region. The rating for astrogliosis was based on the extent of GFAP immunoreactivity (number of GFAP immunoreactive cells and complexity of astrocytic branching). The rating was done by an observer blinded to the treatment status of the mice.

[0294] All statistical analyses of total amyloid burden and astrogliosis were performed using Prism 6.0 (Graphpad, San Diego, Calif., USA).

Results

[0295] Histological Quantification of Amyloid Burden:

[0296] Total amyloid burden in the cortex and dentate gyrus of the hippocampus of ABPP095-PP013 treated mice versus (ZTaq).sub.2-PP013 (control) treated mice were quantified by stereological techniques using random unbiased sampling on the serial sections immunostained with a mixture of 6E10 and 4G8 antibodies. A.beta. immunostaining showed a significant reduction in A.beta. accumulation in both cortical (FIG. 14A-C) and hippocampal (FIG. 15A-C) sections of the ABPP095-PP013 treated mice compared to the control group (p=0.03 and p=0.05 in cortex and hippocampus, respectively).

[0297] Neuroinflammatory Response after Treatment:

[0298] A concern when administrating therapeutics that target A.beta. depositions is the risk of increased brain inflammation, ultimately resulting in neuronal dysfunction or death. To evaluate the effect of ABPP095-PP013 treatment on brain inflammation, the extent of gliosis in the hippocampus and cortex was quantitatively examined by immunohistochemical staining. Histological observation of astrocytes, which were stained with an anti-GFAP antibody, revealed that there was a slight reduction in astrogliosis in the ABPP095-PP013 treated mice compared to the control treated group, although the observed differences were not significant (FIG. 16A-C). Most importantly, no increased risk of brain inflammation was observed in association with ABPP095-PP013 treatment.

Example 10

Extraction of Soluble and Insoluble A.beta. from Alzheimer's Disease Model Mice Treated with A.beta. Peptide Binding Polypeptides

Summary

[0299] This Example describes the assessment of total soluble A.beta. and A.beta. aggregates/oligomers in the brain of (2.times.Tg) sweAPP/PS1 mice sacrificed after the behavioral study described in Example 8 and studied histologically as described in Example 9.

Materials and Methods

[0300] The left hemisphere of each brain was weighed and homogenized (10 w/v) in tissue homogenization buffer (20 mM Tris base, pH 7.4, 250 mM sucrose, 1 mM EDTA, 1 mM EGTA) with 100 mM phenylmethylsulphonyl fluoride, complete protease inhibitor cocktail and PhosSTOP phosphatase inhibitor cocktail (Roche) added immediately before homogenization. The extraction of soluble A.beta. and total A.beta. was done according to the method published previously (Boutajangout et al (2009) supra; Scholtzova et al (2009) supra; Goni et al (2010) PLoS One 5:e13391; Yang et al 2011 supra; Liu et al 2014, supra).

[0301] In brief, a first brain homogenate (200 .mu.l) was mixed with an equal volume of cold 0.4% diethylamine (DEA)/100 mM NaCl, and subsequently centrifuged at 100000 g for 1 h at 4.degree. C. The obtained supernatant was neutralized with 1/10 volume of 0.5 M Tris, pH 6.8, flash-frozen on dry ice and stored at -80.degree. C. until used as soluble A.beta. fraction.

[0302] A second homogenate (200 .mu.l) was added to 440 .mu.l of cold formic acid (FA) and sonicated for 1 min on ice. Subsequently, 400 .mu.l of this solution was centrifuged at 100000 g for 1 h at 4.degree. C. and 210 .mu.l of the resulting supernatant was diluted into 4 ml of FA neutralization solution (1 M Tris base, 0.5 M Na.sub.2HPO.sub.4, 0.05% NaN.sub.3), flash-frozen on dry ice and stored at -80.degree. C. until used for total A.beta. measurement.

[0303] Levels of soluble and total A.beta. using DEA and FA extracts, respectively, are determined by a sandwich Enzyme-Linked Immuno Sorbent Assay (ELISA) for instance as described in Scholtzova et al (2009, supra). Preparations of samples and measurements of levels of A.beta. oligomers and A.beta. aggregates in the brain are determined for example as described in Scholtzova et al (2014, Acta Neuropathologica Communications 2:101) and Liu et al 2014, supra) including western blot analysis using antibodies specific for A.beta. oligomers/aggregates (for example A11 polyclonal antibody (Invitrogen)) and analysis by a Human Aggregated A.beta. ELISA kit (Invitrogen) according to the manufacturer's instructions.

Results

[0304] The results are expected to show reduced levels of total and soluble A.beta. as well as reduced levels of A.beta. aggregates/oligomers in brains from ABPP095-PP013 treated mice compared to brains from mice treated with the control polypeptide (ZTaq).sub.2-PP013.

Example 11

Measurement of Plasma Levels of A.beta. Peptide Binding Polypeptides

Summary

[0305] This Example describes the assessment of plasma levels of ABPP095-PP013 and (ZTaq).sub.2-PP013 in the (2.times.Tg) sweAPP/PS1 mice studied in Example 8.

Materials and Methods

[0306] The mice were bled before the commencement of the behavioral study described in Example 8 as well as periodically throughout the study. Plasma levels of ABPP095-PP013 and (ZTaq).sub.2-PP013 are detected by ELISA using plates (Immulon 2HB; Thermo Electron Corp) coated with 0.5 .mu.g/well of A.beta..sub.1-40 peptide (synthesized at the Keck Foundation at Yale University). Detection is performed using a primary polyclonal goat anti-Z IgG (in-house produced) at a dilution of 1/1000 and subsequently by a labeled secondary antibody, for example an anti-goat IgG-HRP (Jackson). Plates are developed with TMB substrate and the reactions are stopped with 2M H.sub.2SO.sub.4 followed by absorbance measurements at 450 nm.

Results

[0307] The results are expected to show the levels of ABPP095-PP013 and (ZTaq).sub.2-PP013 over time in plasma samples obtained from treated (2.times.Tg) sweAPP/PS1 mice.

Example 12

Inhibition of A.beta. Aggregation by A.beta. Peptide Binding Polypeptides Studied by Thioflavin Fluorescence Assay

Summary

[0308] In Alzheimer's disease (AD), the A.beta. peptide is prone to aggregate. The course of events can be studied in vitro with methods such as the thioflavin T (ThT) fluorescence assay (Hellstrand et al (2009), ACS Chem. Neurosci. 1:13-18). This assay measures changes of in fluorescence intensity of ThT upon binding to amyloid fibrils. The enhanced fluorescence can be observed by fluorescence spectroscopy. The capacity of A.beta. peptide binding polypeptides as disclosed herein to inhibit A.beta. peptide aggregation is tested in the ThT assay.

Materials and Methods

[0309] Monomeric A.beta..sub.1-40 or A.beta..sub.1-42 at various concentrations is mixed with 20 .mu.M ThT (Sigma) in a 20 mM sodium phosphate buffer supplemented with 200 .mu.M EDTA. The preparation is done in black polystyrene ELISA plates with clear bottom and on ice. The aggregation is triggered by placing 96 well plates at 37.degree. C. and shaking at 100 rpm. The ThT fluorescence is measured using 440 and 480 nm excitation and emission filters, respectively, in an Enspire plate reader (Perkin Elmer). The fluorescence is initially measured over a time period to find out the optimal A.beta. peptide concentration and the time needed to reach maximal aggregation. The ability of an A.beta. peptide binding polypeptide as disclosed herein to block aggregation is tested by mixing the A.beta. peptide binding polypeptide at various concentrations together with the optimized A.beta.:ThT ratio and then reading the fluorescence as described above.

Results

[0310] The results are expected to show that A.beta. peptide binding polypeptides as disclosed herein block the aggregation of A.beta. peptide in vitro as measured by the ThT aggregation assay.

Example 13

Inhibition of A.beta. Aggregation by A.beta. Peptide Binding Polypeptides Studied by Fluorescence Correlation Spectroscopy (FCS)

Materials and Methods

[0311] Sample preparation: A.beta..sub.40 (AlexoTech AB, Umea, Sweden) was freshly prepared by dissolving the peptide powder on ice in 10 mM NaOH to a concentration of 1.0 mg/ml, followed by dilution in 20 mM HEPES, pH 7.0 as required. Fluorescently labeled opioid peptides, custom synthesized and purified >98% (Biomatik), were added to the freshly prepared solution of unlabeled A.beta..sub.40 and the concentration was confirmed by FCS immediately after mixing. The time course of A.beta..sub.40 aggregation was monitored in a solution containing 10 .mu.M unlabeled A.beta..sub.40, 100 nM A.beta..sub.40-Alexa488 and 100 nM A.beta..sub.40-Alexa647 in 20 mM HEPES, pH 7.0, T=20.degree. C. in the presence or absence of 20 .mu.M of the A.beta. binding polypeptide ABPP095 (SEQ ID NO:95).

[0312] FCS Measurements:

[0313] FCS measurements were performed on a uniquely modified ConfoCor3 instrument (Carl Zeiss, Jena, Germany) consisting of an inverted microscope for transmitted light and epifluorescence (Axiovert 200 M); a VIS-laser module comprising the Ar/ArKr (458, 477, 488 and 514 nm), HeNe 543 nm and HeNe 633 nm lasers; and the scanning module LSM 510 META. The instrument was modified to enable detection using silicon Avalanche Photo Detectors (SPCM-AQR-1X; PerkinElmer, USA) for imaging and FCS (Vukojevic et al (2008), Proc Natl Acad Sci 105:18176-18181). The C-Apochromat 40.times., NA=1.2, water immersion UV-VIS-IR objective was used throughout. Alexa488 was excited using the 488 nm line of the Ar/ArKr laser, whereas the HeNe633 laser was used to excite Alexa647. The main dichroic beam splitter HFT 488/543/633 was used to separate the incident and fluorescence light. Fluorescence signals were separated using a secondary dichroic beam splitter (NFT 635) and further spectrally narrowed before detection using a band pass filter (BP 505-610) for Alexa488 and a long pass filter (LP 650) for Alexa647.

[0314] Fluorescence intensity fluctuations were recorded at approximately 10 min intervals in arrays of 30 consecutive measurements, each measurement lasting 10 s, and analyzed by temporal autocorrelation analysis. Autocorrelation curves were analyzed using the online software for data analysis and the generated autocorrelation curves were fitted with a model for free 3D diffusion of one component. Fitting was performed using the dedicated routine that is part of the running software and the quality of fitting was evaluated by residuals analysis.

Results

[0315] Fluorescence correlation spectroscopy was applied to study A.beta..sub.40 aggregation in solution over time, in the presence or absence of the A.beta. binding polypeptide ABPP095. The results showed that the propensity of A.beta..sub.40 to aggregate decreased in the presence of ABPP095. A diffusion time analysis, monitoring changes in the distribution of diffusion times, which reflects changes in aggregate size, is presented in FIG. 17. In the absence of ABPP095, a spread in diffusion times (.tau..sub.D) appeared after about 1 h, whereas in the presence of ABPP095 the diffusion times remained low.

Example 14

Intranasal Administration of A.beta. Peptide Binding Polypeptides

Summary

[0316] Intranasal drug administration is an attractive route for delivery of compounds to the central nervous system (CNS). Efficacy of intranasally administered proteins has been demonstrated in a variety of rodent disease models (Thorne et al, (2004), Neuroscience, 127:481-496; De Rosa et al (2005), Proc. Natl. Acad. Sci. 102:3811-3816; Topkuru et al (2013), Stroke, 44:3189-3194; Lochhead et al, (2015), J Cereb. Blood Flow Met. 35:371-381) as well as in humans (reviewed in Lochhead and Thorne (2012), Adv. Drug Deliv. Rev. 64:614-628). Intranasal administration is therefore evaluated for delivery of A.beta. peptide binding polypeptides to the brain and cerebrospinal fluid (CSF). Furthermore, in contrast to systemic injection, intranasal administration also avoids high exposure in the blood circulation, thus lowering the probability of systemic side effects.

Materials and Methods

[0317] Prebleeds of all animals, such as Sprague Dawley rats (from an accredited vendor), are collected ten days before dosing. Intranasal administration is carried out under isoflurane anesthesia. The animals are placed in a supine position and a total of 60 .mu.l (1000 .mu.g) A.beta. peptide binding polypeptide, alone or in fusion with the albumin binding domain PP013 (SEQ ID NO:107), is administered by pipette in 10 .mu.l drops, treating each nare every 2.5 min over a total of 10 min. 3 mM Pz-peptide (4-phenylazobenzoxy-carbonyl-Pro-Leu-Gly-Pro-DArg; Bachem) may be included in the A.beta. peptide binding polypeptide formulation as a penetration enhancer. Animals are anaesthetized and sacrificed at 0.5, 2, 6, and 24 h after the first intranasal instillation. Blood samples are collected and the rats are then anesthetized using ketamine+xylazine/medetomidine for collection of CSF. After euthanization the rats are perfused with ice cold PBS and the olfactory bulbs are carefully harvested. The tissues are weighed, frozen on dry ice and stored at -80.degree. C. until analysis. Brain tissues are prepared by addition of a lysis buffer followed by sonication. Cell debris is removed by centrifugation and the supernatant and CSF are subjected to an ELISA based determination of A.beta. peptide binding polypeptide concentrations, for example as described in Example 11. The same ELISA method is applied to analyze serum from collected blood samples to evaluate the systemic exposure.

Results

[0318] The results are expected to show significant concentrations of A.beta. peptide binding polypeptide in the olfactory bulb. The concentration in CSF and blood are expected to be low in concordance with Furrer et al (2009, J Neuroimmunol 215:65-72) and Thorne et al (supra). The olfactory bulb is connected with the nasal cavity through the olfactory system, and the brainstem is connected with the nasal passages through the peripheral trigeminal system. The delivery of A.beta. peptide binding polypeptide to the CNS is expected to be much more efficient following intranasal administration than following a dose adjusted (for instance adjusted to obtain the same systems exposure) intravenous injection where penetration across the blood brain barrier is necessary.

Example 15

Characterization of A.beta. Peptide Binding Polypeptides with an Alternative Scaffold

Summary

[0319] This Example describes the adaptation of the binding parts of A.beta. peptide binding polypeptide ABPP095 in alternative scaffold sequences, as well as the analysis of such alternative sequences by circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR).

Materials and Methods

[0320] Cloning of scaffold mutated variants of ABPP095: ABPP095 with a C-terminal His.sub.6 tag (as used in Example 5 and 6) was further modified at scaffold positions, symmetrically within both moieties. Introduced mutations are listed in Table 5. Synthetic genes were ordered from DNA2.0. From the delivered plasmids, the DNA sequences encoding the polypeptides were cleaved and subsequently ligated into the expression vector pET26b+(Novagen) using the NdeI and XhoI restriction sites. The generated constructs with a C-terminal His.sub.6 tag were in the general format ABPP095#-LEHHHHHH.

TABLE-US-00012 TABLE 5 Scaffold mutations within ABPP095 SEQ ID Mutations Designation NO: in moiety 1 Mutations in moiety 2 ABPP095a 551 N41S, D42E N101S, D102E ABPP095b 552 A31S, N32E, A35S, A91S, N92E, A95S, N41S, D42E, A43S N101S, D102E, A103S ABPP095c 553 N12T, S22K, A31S, N72T, S82K, A91S, N92E, N32E, A35S, N41S, A95S, N101S, D102E, D42E, A43S A103S

[0321] Production of Scaffold Mutated Variants of ABPP095:

[0322] E. coli T7E2 cells (GeneBridges) were transformed with plasmids containing the gene fragments of each respective ABPP095 variant and cultivated in a fermenter (GRETA4, Belach Bioteknik AB) at 37.degree. C. in approximately 940 ml of TSB-YE medium supplemented with 50 .mu.g/ml kanamycin. In order to induce protein expression, IPTG was added to a final concentration of 0.17 mM at OD.sub.600=2 and the cultivation was incubated at 37.degree. C. for another 5 h. The cells were harvested by centrifugation.

[0323] Approximately 4 g of each cell pellet was re-suspended in 13 ml [20 mM sodium phosphate, 0.5 M NaCl, 20 mM imidazole, pH 7.4] and Benzonase.RTM. (Merck, cat. no. 1.01654.0001) was added to a concentration of approximately 90 U/ml. The cell suspension was transferred to 10 g Lysing Matrix B (MP Biomedicals, cat.no. 116540429) and the cells were disrupted using a FastPrep.RTM.-24 Instrument (MP Biomedicals). Cell debris was removed by centrifugation and each supernatant was applied on a 1 ml His GraviTrap IMAC column (GE Healthcare, cat. no. 11-0033-99). Contaminants were removed by washing with wash buffer (20 mM sodium phosphate, 0.5 M NaCl, 60 mM imidazole, pH 7.4) and the ABPP095 variants were subsequently eluted with 3 ml elution buffer (20 mM sodium phosphate, 0.5 M NaCl, 500 mM imidazole, pH 7.4). For reduction of disulfides, dithiothreitol (DTT) was added to a final concentration of 20 mM followed by incubation at RT for 1 h. Buffer exchange to [20 mM Tris-HCl, 150 mM NaCl, pH 8.0] was carried out using PD-10 Desalting columns (GE Healthcare, cat.no. 17-0851-01) and the samples were diluted to 0.2 mg/ml in the same buffer. Reduced glutathione (GSH; Sigma, cat. no. G-4251) and oxidized glutathione (GSSG; Sigma, cat. no. G-4376) was added to a concentration of 2 mM and 0.4 mM, respectively, followed by overnight incubation in the dark at 4.degree. C. Each sample was further purified by reverse phase chromatography (RPC) using a 1 ml Resource RPC column (GE Healthcare, cat.no 17-1181-01) connected to an AKTAexplorer 10 system (GE Healthcare). Acetonitrile (ACN) was supplemented to a final concentration of 10% and the sample was loaded on the Resource RPC column equilibrated with Solvent A (10% ACN, 0.1 trifluoroacetic acid (TFA) in Milli-Q water). The column was washed with 5 CV of Solvent A prior to elution by a 0-60% linear gradient of Solvent B (80 ACN, 0.1% TFA in Milli-Q water) over 18 column volumes. Finally, buffer exchange to DPBS (Corning, cat. no. 21-031-CVR) was carried out using PD-10 Desalting columns.

[0324] For each protein, the concentration was determined by measuring the absorbance at 280 nm, using a NanoDrop.RTM. ND-1000 spectrophotometer and the extinction coefficient of the protein. The purity was analyzed by SDS-PAGE stained with Coomassie Blue and the identity of each purified ABPP095 variant was confirmed using HPLC-MS analysis (HPLC-MS 1100; Agilent Technologies).

[0325] Circular Dichroism Spectroscopy:

[0326] CD analysis was performed essentially as described in Example 6, but using a protein concentration of 0.5 mg/ml.

[0327] Biacore Kinetic Analysis:

[0328] Rough kinetic constants (k.sub.a and k.sub.d) and affinities (K.sub.D) for human A.beta..sub.1-40, (hA.beta..sub.1-40), human A.beta..sub.1-42 (hA.beta..sub.1-42) and mouse A.beta..sub.1-40 (mA.beta..sub.1-40) were determined for ABPP095 (SEQ ID NO:95), its scaffold mutated derivatives ABPP095a (SEQ ID NO:551), ABPP095b (SEQ ID NO:552) and ABPP095c (SEQ ID NO:553) as well as for ABPP095-PP013 (SEQ ID NO:115) using a Biacore 2000 instrument (GE Healthcare). N-terminally biotinylated hA.beta..sub.1-40 (AnaSpec, cat. no. AS-24648), hA.beta..sub.1-42 (AnaSpec, cat. no. AS-24641-01) and mA.beta..sub.1-40 (AnaSpec, cat. no. AS-61717-01) were immobilized in separate flow cells on a streptavidin coated chip (Biacore Sensor Chip SA, cat. no. BR100032) and using HBS-EP as running buffer (0.01 M HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.005% v/v Surfactant P20, GE Healthcare, cat. no. BR100188). The ligand immobilization levels on the surfaces were 17 RU for hA.beta..sub.1-40, 16 RU for hA.beta..sub.1-42 and 22 RU for mA.beta..sub.1-40. One flow cell surface on the chip was used as blank during analyte injections. HBS-EP was used as running buffer and the flow rate was 30 .mu.l/min. The analytes, i.e. A.beta. peptide binding polypeptides, were each diluted in HBS-EP buffer to concentrations of 630, 210, 70, 23 and 8 nM and injected for 6 min, followed by dissociation in running buffer for 40 min. After dissociation, the surfaces were regenerated with 10 mM glycin pH 2.0. Kinetic constants were calculated from the sensorgrams using the Langmuir 1:1 model of BiaEvaluation software 4.1 (GE Healthcare).

Results

[0329] Production of Scaffold Mutated Variants of ABPP095:

[0330] All variants were expressed as soluble gene products in E. coli. SDS-PAGE analysis of each final protein preparation showed >98% purity. The correct oxidized monomer identity was confirmed by HPLC-MS analysis.

[0331] CD Analysis:

[0332] The melting temperatures (Tm) were determined using variable temperature measurements and showed that the Tm of the scaffold mutated variants were similar to the Tm of ABPP095 (Table 6). Reversible folding was observed for all mutated variants when overlaying spectra measured at 20.degree. C. before and after heating to 90.degree. C.

TABLE-US-00013 TABLE 6 Melting temperatures of scaffold mutated ABPP095 variants Designation SEQ ID NO: Tm (.degree. C.) ABPP095 95 43 ABPP095a 551 45 ABPP095b 552 45 ABPP096c 553 44

[0333] SPR Kinetic Analysis:

[0334] The interactions of ABPP095, its scaffold mutated derivatives ABPP095a, ABPP095b and ABPP095c as well as ABPP095-PP013, with hA.beta..sub.1-40, hA.beta..sub.1-42 and mA.beta..sub.1-40 were analyzed in a Biacore instrument by injecting various concentrations of the A.beta. peptide binding polypeptides over a surface containing the respective A.beta. peptide. All tested A.beta. peptide binding polypeptides showed binding to the respective A.beta. peptide variant. A summary of the kinetic parameters (K.sub.D, k.sub.a and k.sub.d) obtained using a 1:1 interaction model is given in Table 7.

TABLE-US-00014 TABLE 7 Kinetic data for binding to different A.beta. peptides SEQ ID K.sub.D k.sub.a k.sub.d Designation NO: Target (M) (M.sup.-1s.sup.-1) (s.sup.-1) ABPP095 95 hA.beta..sub.1-40 5.0 .times. 10.sup.-10 7.5 .times. 10.sup.4 3.8 .times. 10.sup.-5 ABPP095a 551 hA.beta..sub.1-40 4.0 .times. 10.sup.-9 7.4 .times. 10.sup.4 3.0 .times. 10.sup.-4 ABPP095b 552 hA.beta..sub.1-40 1.3 .times. 10.sup.-8 5.0 .times. 10.sup.4 6.8 .times. 10.sup.-4 ABPP095c 553 hA.beta..sub.1-40 2.3 .times. 10.sup.-9 8.1 .times. 10.sup.4 1.9 .times. 10.sup.-4 ABPP095- 115 hA.beta..sub.1-40 2.7 .times. 10.sup.-9 1.7 .times. 10.sup.4 4.7 .times. 10.sup.-5 PP013 ABPP095 95 hA.beta..sub.1-42 3.3 .times. 10.sup.-10 1.2 .times. 10.sup.5 4.1 .times. 10.sup.-5 ABPP095a 551 hA.beta..sub.1-42 5.0 .times. 10.sup.-9 1.2 .times. 10.sup.5 6.2 .times. 10.sup.-4 ABPP095b 552 hA.beta..sub.1-42 1.5 .times. 10.sup.-8 1.0 .times. 10.sup.5 1.5 .times. 10.sup.-3 ABPP095c 553 hA.beta..sub.1-42 2.6 .times. 10.sup.-9 1.4 .times. 10.sup.5 3.6 .times. 10.sup.-4 ABPP095- 115 hA.beta..sub.1-42 2.3 .times. 10.sup.-9 2.2 .times. 10.sup.4 4.9 .times. 10.sup.-5 PP013 ABPP095 95 mA.beta..sub.1-40 1.8 .times. 10.sup.-10 1.0 .times. 10.sup.5 1.9 .times. 10.sup.-5 ABPP095a 551 mA.beta..sub.1-40 2.5 .times. 10.sup.-9 1.0 .times. 10.sup.5 2.6 .times. 10.sup.-4 ABPP095b 552 mA.beta..sub.1-40 8.7 .times. 10.sup.-9 7.6 .times. 10.sup.4 6.6 .times. 10.sup.-4 ABPP095c 553 mA.beta..sub.1-40 1.5 .times. 10.sup.-9 1.0 .times. 10.sup.5 1.5 .times. 10.sup.-4 ABPP095- 115 mA.beta..sub.1-40 1.3 .times. 10.sup.-9 2.4 .times. 10.sup.4 3.0 .times. 10.sup.-5 PP013

Example 16

Analysis of Additional A.beta. Peptide Binding Polypeptides

Materials and Methods

[0335] Subcloning of A.beta. Peptide Binding Polypeptides for Screening:

[0336] Separate mixes of clones from each library (i.e the symmetric and the asymmetric library, respectively) obtained from the third rounds of cell sorting described in Example 2, were PCR amplified, restricted using endonucleases AccI and XhoI and ligated into the phagemid vector pAY02592 (essentially as described in Gronwall et al., supra) restricted using the same endonucleases. Transformations of the ligations were made into electrocompetent E. coli ER2738 (Lucigen).

[0337] Sequencing:

[0338] All individual clones were sequenced. PCR fragments were amplified from single colonies, sequenced and analyzed essentially as described in WO2009/077175.

[0339] Production of A.beta. Peptide Binding Polypeptides for ELISA:

[0340] Sequenced A.beta. peptide binding polypeptides were produced by inoculating single colonies from the bulk cloning in 1.2 ml TSB-YE medium supplemented with 100 .mu.g/ml ampicillin and 0.1 mM IPTG in deep-well plates (Nunc, cat. no. 278752). The plates were incubated for 24 h at 37.degree. C. Cells were pelleted by centrifugation, re-suspended in 150 .mu.l PBST 0.05% (PBS supplemented with 0.05% Tween-20) and incubated at 82.degree. C. in a water bath for 20 min. Cell suspensions were transferred to 96-well filtration plates (MerckMillipore, cat. no. MSNANLY50) and spun in a centrifuge at 1500.times.g for 4 min and the permeates were collected in new 96-well plates.

[0341] The supernatant of the periplasmic extract contained the A.beta. peptide binding polypeptides as fusions to the albumin binding domain corresponding to GA.beta. of protein G from Streptococcus strain G148, here denoted ABD, expressed as AQHDEALE-[ABPP###]-VDYV-[ABD]-YVPG (Gronwall et al., supra). ABPP### refers to individual, 107 amino acid residue A.beta. peptide binding polypeptides.

[0342] ELISA Analysis of A.beta. Peptide Binding Polypeptides:

[0343] The binding of A.beta. peptide binding polypeptides to A.beta..sub.1-40 was analyzed in a sandwich ELISA. Half-area 96-well ELISA plates (Costar, cat. no. 3690) were coated at 4.degree. C. overnight with 2 .mu.g/ml of an anti-ABD goat antibody (produced in-house) diluted in coating buffer (50 mM sodium carbonate, pH 9.6; Sigma, cat. no. C3041). The wells were blocked with 100 .mu.l of PBSC (PBS supplemented with 0.5% casein; Sigma, cat. no. C8654) and 50 .mu.l periplasmic solution was added to the wells and incubated for 30 min at RT. The wells were washed 4 times with PBST 0.05% whereafter 50 .mu.l of N-terminally biotinylated hA.beta..sub.1-40 (AnaSpec, cat. no. AS-24648) at a concentration of 2 nM in PBSC was added to each well. The plates were incubated for 75 min at RT followed by 4 washes and addition of streptavidin conjugated HRP (Thermo Scientific, cat. no. N100) diluted 1:30000 in PBSC. The plates were incubated for 30 min whereafter they were washed as described above. The plates were developed by addition of 50 .mu.l 1-Step Ultra TMB (Thermo Scientific, cat. no. 34028) according to the manufacturer's recommendations.

[0344] The periplasmic fraction of the A.beta. peptide binding polypeptide ABPP095 (SEQ ID NO:95) was used in duplicate as positive control on each ELISA plate. A negative control was created using ABD periplasm assayed against biotinylated hA.beta..sub.1-40. The absorbance at 450 nm was measured using a multi-well plate reader (EnSpire; Perkin Elmer).

[0345] ELISA EC50 Analysis of A.beta. Peptide Binding Polypeptides:

[0346] A selection of A.beta. peptide binding polypeptides was subjected to an analysis of the response against a dilution series of biotinylated hA.beta..sub.1-40 using ELISA essentially as described above. The assay was performed in 384-well high binding assay plates (Greiner, cat. no. 781061). Biotinylated protein was added at a concentration of 150 nM and diluted stepwise 1:5 down to 240 pM. All A.beta. peptide binding polypeptides were also assayed without added target protein as a background control. Periplasm samples containing the A.beta. peptide binding polypeptide ABPP095 were included and analyzed as a positive control. As a negative control, periplasm containing ABD only was assayed against the same target. Obtained values were analyzed using GraphPad Prism 5 and non-linear regression and EC50 values (the half maximal effective concentration) were calculated.

[0347] SPR Analysis of Periplasmic Samples:

[0348] A selection of A.beta. peptide binding polypeptides was subjected to an analysis of the response against biotinylated hA.beta..sub.1-40 using a Biacore 2000 instrument (GE Healthcare). Biotinylated anti-ABD goat antibody (produced in-house) and N-terminally biotinylated hA.beta..sub.1-40 (AnaSpec cat. no. AS-24648) were immobilized in separate flow cells on a streptavidin coated chip (Biacore Sensor Chip SA, cat. no. BR100032) using HBS-EP as running buffer (0.01 M HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.005% v/v Surfactant P20, GE Healthcare, cat. no. BR100188). The ligand immobilization levels on the surfaces were approximately 2000 RU for the anti-ABD antibody and 225 RU for hA.beta..sub.1-40. One flow cell surface on the chip was used as blank during analyte injections. HBS-EP was used as running buffer and the flow rate was 25 .mu.l/min. The analytes, i.e. periplasmic preparations of A.beta. peptide binding polypeptides as described above, were each diluted 15.times. in HBS-EP buffer and injected for 10 min, followed by dissociation in running buffer for 5 min. After dissociation, the surfaces were regenerated with 2 pulses of 10 mM glycin pH 2.0. ABPP095 was included as first sample, in the middle and as last sample, as a reference in the analysis to ensure the stability of the surfaces and was in total run 6 times. Samples of ABD were included as blank control for the hA.beta..sub.1-40 surface.

Results

[0349] Subcloning of A.beta. Peptide Binding Polypeptides for Screening:

[0350] From the third round of cell sorting described in Example 2, clones were subcloned in bulk to the vector pAY02592. The outcomes of the two different libraries were kept separate and clones were transformed to E. coli ER2738.

[0351] Sequencing:

[0352] Sequencing was performed after subcloning of individual colonies for identification. Out of a total of 1116 sequences (558 per library), 185 new unique polypeptide variants were identified in the output from the asymmetric library and 254 unique polypeptide variants were identified in the output from the symmetric library. Of these, 5 variants were identified in the output from both libraries. In addition, 51 polypeptide variants (21 from the asymmetric library and 30 from the symmetric library) already identified in the first screening described in Example 2 were picked up again.

[0353] ELISA Analysis of A.beta. Peptide Binding Polypeptides:

[0354] The clones obtained after subcloning in bulk of the outcome after three rounds of cell sorting were produced in 96-well plates and screened for A.beta. binding activity in ELISA. The average response of the negative controls was 0.063 AU. The majority of the A.beta. peptide binding polypeptides were found to give a response of 0.2 AU or higher (corresponding to at least 3.times. the negative control) against hA.beta..sub.1-40 at a concentration of 2 nM. The amino acid sequences of those among these polypeptides which were newly identified (not included after the first screen of Example 2) are listed in FIG. 1 as SEQ ID NO:118-550. Polypeptide variants identified in the output from the asymmetric library are listed in FIG. 1 as SEQ ID NO:139-142, 155-159 and 376-550, and polypeptide variants identified in the output from the symmetric library are listed in FIG. 1 as SEQ ID NO:118-138, 143-154 and 160-374. The polypeptides with SEQ ID NO:229, 233, 248, 321 and 334 were identified in the output from both libraries.

[0355] ELISA EC50 Analysis of A.beta. Peptide Binding Polypeptides:

[0356] A subset of A.beta. peptide binding polypeptides was selected based on the result in the ELISA experiment described above and subjected to a target titration in ELISA format. Periplasm samples were incubated with a serial dilution of biotinylated hA.beta..sub.1-40. A periplasm sample with the A.beta. peptide binding polypeptide ABPP095 (SEQ ID NO:95) was also assayed as a positive control. Obtained values were analyzed and their respective EC50 values were calculated (Table 8).

TABLE-US-00015 TABLE 8 EC50 values of polypeptides binding to hA.beta..sub.1-40 SEQ ID EC50 Designation NO: (M) ABPP107 118 4.8 .times. 10.sup.-9 ABPP108 119 5.8 .times. 10.sup.-9 ABPP109 120 5.0 .times. 10.sup.-9 ABPP111 122 1.4 .times. 10.sup.-8 ABPP112 123 4.6 .times. 10.sup.-9 ABPP113 124 3.8 .times. 10.sup.-9 ABPP115 126 3.9 .times. 10.sup.-9 ABPP116 127 3.7 .times. 10.sup.-9 ABPP117 128 6.4 .times. 10.sup.-9 ABPP118 129 5.2 .times. 10.sup.-9 ABPP119 130 3.9 .times. 10.sup.-9 ABPP120 131 3.5 .times. 10.sup.-9 ABPP121 132 5.9 .times. 10.sup.-8 ABPP122 133 5.2 .times. 10.sup.-9 ABPP123 134 5.4 .times. 10.sup.-9 ABPP124 135 1.3 .times. 10.sup.-8 ABPP125 136 4.3 .times. 10.sup.-9 ABPP126 137 5.9 .times. 10.sup.-9 ABPP127 138 5.7 .times. 10.sup.-9 ABPP128 139 5.2 .times. 10.sup.-9 ABPP129 140 9.0 .times. 10.sup.-9 ABPP130 141 6.0 .times. 10.sup.-9 ABPP131 142 6.8 .times. 10.sup.-9 ABPP132 143 8.1 .times. 10.sup.-9 ABPP133 144 4.2 .times. 10.sup.-7 ABPP134 145 2.7 .times. 10.sup.-8 ABPP135 146 6.3 .times. 10.sup.-9 ABPP136 147 7.9 .times. 10.sup.-9 ABPP137 148 8.4 .times. 10.sup.-9 ABPP139 150 8.4 .times. 10.sup.-9 ABPP140 151 4.1 .times. 10.sup.-8 ABPP143 154 9.3 .times. 10.sup.-9 ABPP144 155 1.6 .times. 10.sup.-8 ABPP145 156 9.4 .times. 10.sup.-9 ABPP146 157 8.6 .times. 10.sup.-9 ABPP147 158 7.9 .times. 10.sup.-9 ABPP148 159 6.0 .times. 10.sup.-9 ABPP049 49 7.1 .times. 10.sup.-9 ABPP051 51 4.6 .times. 10.sup.-9 ABPP055 55 2.8 .times. 10.sup.-9 ABPP059 59 1.3 .times. 10.sup.-8 ABPP064 64 4.0 .times. 10.sup.-9 ABPP065 65 1.3 .times. 10.sup.-8 ABPP072 72 8.5 .times. 10.sup.-9 ABPP078 78 3.0 .times. 10.sup.-8 .sup.1Analyzed in duplicate

[0357] SPR Analysis of Periplasmic Samples:

[0358] The interactions of a subset of Z variants with anti-ABD goat antibody and hA.beta..sub.1-40 were analyzed in a Biacore instrument by injecting dilutions of periplasmic samples. The responses against the two surfaces were monitored and are shown in Table 9. The response against the anti-ABD goat antibody shows the relative amount of Z variant in the periplasmic sample and the response against the hA.beta..sub.1-40 shows the binding capability of each variant in that relative dilution.

TABLE-US-00016 TABLE 9 Relative responses in SPR analysis SEQ ID Anti-ABD surface hA.beta..sub.1-40 Designation NO: (Response RU) (Response RU) ABPP107 118 42.2 15.6 ABPP108 119 41.5 15.2 ABPP109 120 42.0 20.2 ABPP110 121 37.5 13.8 ABPP111 122 35.6 14.2 ABPP112 123 48.1 12.1 ABPP113 124 42.0 20.2 ABPP114 125 50.9 34.1 ABPP115 126 39.7 13.3 ABPP116 127 40.0 15.1 ABPP117 128 31.6 9.7 ABPP118 129 41.2 19.2 ABPP119.sup.1 130 31.8 .+-. 1.5 15.6 .+-. 1.5 ABPP120 131 37.7 13.1 ABPP121 132 47.4 47.5 ABPP122 133 47.6 30.1 ABPP123 134 38.8 15.5 ABPP124 135 41.0 23.3 ABPP125 136 38.6 18.4 ABPP126 137 37.8 17.8 ABPP127 138 31.9 9.1 ABPP128 139 48.7 33.0 ABPP129 140 43.6 35.8 ABPP130 141 44.6 21.0 ABPP131 142 34.7 18.9 ABPP132 143 45.3 23.0 ABPP133 144 38.9 14.5 ABPP134 145 40.8 10.3 ABPP135 146 35.0 14.9 ABPP136 147 39.5 13.7 ABPP137 148 35.2 15.3 ABPP138 149 37.8 10.1 ABPP139 150 32.7 10.4 ABPP140 151 36.5 12.3 ABPP141 152 31.5 10.5 ABPP142 153 32.2 9.5 ABPP143 154 31.7 15.8 ABPP144 155 32.1 10.0 ABPP145 156 34.3 15.2 ABPP146 157 36.7 15.2 ABPP147 158 39.2 17.0 ABPP148 159 28.7 10.2 ABPP035 35 31.8 8.6 ABPP049 49 30.6 13.7 ABPP051 51 51.5 21.4 ABPP055.sup.1 55 37.0 .+-. 1.1 18.2 .+-. 4.9 ABPP059 59 39.5 15.4 ABPP064 64 38.8 12.0 ABPP065 65 39.1 8.4 ABPP070 70 40.7 16.6 ABPP072 72 39.7 10.1 ABPP078 78 38.6 12.5 ABPP095.sup.2 95 40.6 .+-. 2.2 24.6 .+-. 0.5 ABD.sup.1,3 117 19.8 .+-. 1.3 2.0 .+-. 0.3 .sup.1Analyzed 2 times, average presented .sup.2Analyzed 6 times, average presented .sup.3Lower molecular weight, hence lower RU expected

Itemized List of Embodiments

[0359] 1. A.beta. peptide binding polypeptide, which comprises [0360] a first moiety comprising a first A.beta. peptide binding motif BM1, [0361] a second moiety comprising a second A.beta. peptide binding motif BM2, which motifs may be the same or different, and [0362] a linker, [0363] wherein each one of said binding motifs BM1 and BM2 consists of an amino acid sequence selected from [0364] i) EX.sub.2X.sub.3YX.sub.5X.sub.6NLX.sub.9A X.sub.11QLCAX.sub.16IX.sub.18X.sub.19X.sub.20 ED wherein, independently from each other,

[0365] X.sub.2 is selected from I, M, Q, R, T and Y;

[0366] X.sub.3 is selected from H and V;

[0367] X.sub.5 is selected from F, I and L;

[0368] X.sub.6 is selected from P and T;

[0369] X.sub.9 is selected from N and T;

[0370] X.sub.11 is selected from D and H;

[0371] X.sub.16 is selected from F and I;

[0372] X.sub.18 is selected from N, Q and R;

[0373] X.sub.19 is selected from K and S; and

[0374] X.sub.20 is selected from F, I, L and R;

[0375] and [0376] ii) an amino acid sequence which has at least 95% identity to the sequence defined in i).

[0377] 2. A.beta. peptide binding polypeptide according to item 1, wherein sequence i) in BM1 consists of the amino acid sequence

[0378] EX.sub.2X.sub.3YX.sub.5X.sub.6NLX.sub.9A X.sub.11QLCAFIX.sub.18X.sub.19L ED

wherein, independently from each other,

[0379] X.sub.2 is selected from I, M, Q, R and Y;

[0380] X.sub.3 is selected from H and V;

[0381] X.sub.5 is selected from F, I and L;

[0382] X.sub.6 is selected from P and T;

[0383] X.sub.9 is selected from N and T;

[0384] X.sub.11 is selected from D and H;

[0385] X.sub.18 is selected from N, Q and R; and

[0386] X.sub.19 is selected from K and S.

[0387] 3. A.beta. peptide binding polypeptide according to item 2, wherein, independently from each other, X.sub.2 is further selected from I, Q, R and Y; and X.sub.5 is further selected from F and L.

[0388] 4. A.beta. peptide binding polypeptide according to item 2, wherein X.sub.2 is further selected from I, M and R.

[0389] 5. A.beta. peptide binding polypeptide according to any preceding item, wherein sequence i) in BM2 consists of the amino acid sequence

[0390] EX.sub.2VYX.sub.5PNLX.sub.9A X.sub.11QLCAX.sub.16IX.sub.18X.sub.19X.sub.20 ED

wherein, independently from each other,

[0391] X.sub.2 is selected from I, M, Q, R and T;

[0392] X.sub.5 is selected from F and L;

[0393] X.sub.9 is selected from N and T;

[0394] X.sub.11 is selected from D and H;

[0395] X.sub.16 is selected from F and I;

[0396] X.sub.18 is selected from N, Q and R;

[0397] X.sub.19 is selected from K and S; and

[0398] X.sub.20 is selected from F, I, L and R.

[0399] 6. A.beta. peptide binding polypeptide according to item 5, wherein, independently from each other, X.sub.2 is further selected from R and T; and X.sub.5 is L.

[0400] 7. A.beta. peptide binding polypeptide according to item 5, wherein, independently from each other, X.sub.2 is further selected from I, M, Q and R; X.sub.16 is F; and X.sub.20 is L.

[0401] 8. A.beta. peptide binding polypeptide according to any preceding item, wherein at least one of said first and second moieties comprises the amino acid sequence

[0402] X.sub.AGX.sub.B-[BM]

wherein BM is BM1 or BM2 as defined in any one of items 1-7, and, independently of each other,

[0403] X.sub.A is selected from A and S; and

[0404] X.sub.B is selected from G and R.

[0405] 9. A.beta. peptide binding polypeptide according to any one of items 1-7, wherein at least one of first and second moieties comprises a binding module amino acid sequence, Bmod, selected from [0406] iii) [BM]-DX.sub.aSQX.sub.bX.sub.cX.sub.dLLX.sub.e EAKKLX.sub.fX.sub.gX.sub.hQA PX.sub.i wherein BM is BM1 or BM2 as defined in any one of items 1-7, and, independently of each other,

[0407] X.sub.a is selected from P, Q, R and S;

[0408] X.sub.b is selected from N, Q, R and S;

[0409] X.sub.c is selected from A and S;

[0410] X.sub.d is selected from K, N and E;

[0411] X.sub.e is selected from A, S and C;

[0412] X.sub.f is selected from E, N and S;

[0413] X.sub.g is selected from D, E and S;

[0414] X.sub.h is selected from A and S; and

[0415] X.sub.i is selected from no amino acid, A and K,

and [0416] iv) an amino acid sequence which has at least 97% identity to a sequence defined in iii).

[0417] 10. A.beta. peptide binding polypeptide according to item 9, wherein sequence iii) consists of the amino acid sequence

[0418] [BM]-DX.sub.aSQX.sub.bAX.sub.dLLA EAKKLNDAQA PX.sub.i

wherein BM is BM1 or BM2 as defined in any one of items 1-7, and, independently of each other,

[0419] X.sub.a is selected from P, Q, R and S;

[0420] X.sub.b is selected from N, Q, R and S;

[0421] X.sub.d is selected from K and N; and

[0422] X.sub.i is selected from no amino acid, A and K.

[0423] 11. A.beta. peptide binding polypeptide according to item 10, wherein sequence iii) consists of an amino acid sequence selected from

TABLE-US-00017 [BM]-DPSQSANLLAEAKKLNDAQAP; [BM]-DPSQQANLLAEAKKLNDAQAP; [BM]-DSSQSANLLAEAKKLNDAQAP; [BM]-DPSQQAKLLAEAKKLNDAQAP; [BM]-DPSQNANLLAEAKKLNDAQAP; [BM]-DRSQQANLLAEAKKLNDAQAP; [BM]-DQSQRANLLAEAKKLNDAQAP; [BM]-DQSQQANLLAEAKKLNDAQAP; [BM]-DRSQSANLLAEAKKLNDAQAP; [BM]-DRSQRANLLAEAKKLNDAQAP; and [BM]-DRSQNANLLAEAKKLNDAQAP.

[0424] 12. A.beta. peptide binding polypeptide according to item 10, wherein said first moiety comprises a Bmod in which sequence iii) is an amino acid sequence selected from

TABLE-US-00018 [BM1]-DPSQSANLLAEAKKLNDAQAPA; [BM1]-DPSQQANLLAEAKKLNDAQAPA; [BM1]-DSSQSANLLAEAKKLNDAQAPA; [BM1]-DPSQRANLLAEAKKLNDAQAPA; [BM1]-DPSQQAKLLAEAKKLNDAQAPA; [BM1]-DPSQNANLLAEAKKLNDAQAPA; and [BM1]-DRSQNANLLAEAKKLNDAQAPA.

[0425] 13. A.beta. peptide binding polypeptide according to item 10, wherein said second moiety comprises a Bmod in which sequence iii) is an amino acid sequence selected from

TABLE-US-00019 [BM2]-DPSQQANLLAEAKKLNDAQAPK; [BM2]-DPSQSANLLAEAKKLNDAQAPK; [BM2]-DRSQQANLLAEAKKLNDAQAPK; [BM2]-DQSQRANLLAEAKKLNDAQAPK; [BM2]-DQSQQANLLAEAKKLNDAQAPK; [BM2]-DPSQRANLLAEAKKLNDAQAPK; [BM2]-DRSQSANLLAEAKKLNDAQAPK; [BM2]-DRSQRANLLAEAKKLNDAQAPK; [BM2]-DSSQSANLLAEAKKLNDAQAPK; and [BM2]-DPSQNANLLAEAKKLNDAQAPK.

[0426] 14. A.beta. peptide binding polypeptide according to any one of items 8-13, wherein at least one of first and second moieties comprises the amino acid sequence

[0427] X.sub.AGX.sub.B-[BMod]

wherein BMod is as defined in any one of items 9-13, and, independently of each other,

[0428] X.sub.A is selected from A and S; and

[0429] X.sub.B is selected from G and R.

[0430] 15. A.beta. peptide binding polypeptide according to item 14, wherein at least one of said first and second moieties comprises an amino acid sequence selected from

TABLE-US-00020 AGG-[BM]-DPSQSANLLAEAKKLNDAQAP; AGG-[BM]-DPSQQANLLAEAKKLNDAQAP; AGG-[BM]-DSSQSANLLAEAKKLNDAQAP; AGG-[BM]-DPSQRANLLAEAKKLNDAQAP; AGR-[BM]-DPSQSANLLAEAKKLNDAQAP; AGG-[BM]-DPSQQAKLLAEAKKLNDAQAP; AGG-[BM]-DPSQNANLLAEAKKLNDAQAP; AGR-[BM]-DPSQQANLLAEAKKLNDAQAP; AGR-[BM]-DRSQQANLLAEAKKLNDAQAP; AGR-[BM]-DQSQRANLLAEAKKLNDAQAP; AGR-[BM]-DQSQQANLLAEAKKLNDAQAP; AGR-[BM]-DPSQRANLLAEAKKLNDAQAP; AGR-[BM]-DRSQSANLLAEAKKLNDAQAP; SGG-[BM]-DPSQSANLLAEAKKLNDAQAP; AGR-[BM]-DRSQRANLLAEAKKLNDAQAP; AGR-[BM]-DPSQNANLLAEAKKLNDAQAP; AGR-[BM]-DSSQSANLLAEAKKLNDAQAP; and AGR-[BM]-DRSQNANLLAEAKKLNDAQAP.

[0431] 16. A.beta. peptide binding polypeptide according to item 14, wherein said first moiety comprises an amino acid sequence selected from

TABLE-US-00021 AGG-[BM1]-DPSQSANLLAEAKKLNDAQAPA; AGG-[BM1]-DPSQQANLLAEAKKLNDAQAPA; AGG-[BM1]-DSSQSANLLAEAKKLNDAQAPA; AGG-[BM1]-DPSQRANLLAEAKKLNDAQAPA; AGR-[BM1]-DPSQSANLLAEAKKLNDAQAPA; AGG-[BM1]-DPSQQAKLLAEAKKLNDAQAPA; AGG-[BM1]-DPSQNANLLAEAKKLNDAQAPA; AGR-[BM1]-DPSQNANLLAEAKKLNDAQAP; AGR-[BM1]-DSSQSANLLAEAKKLNDAQAP; and AGR-[BM1]-DRSQNANLLAEAKKLNDAQAP.

[0432] 17. A.beta. peptide binding polypeptide according to item 14, wherein said second moiety comprises an amino acid sequence selected from

TABLE-US-00022 AGR-[BM2]-DPSQQANLLAEAKKLNDAQAPK; AGR-[BM2]-DPSQSANLLAEAKKLNDAQAPK; AGR-[BM2]-DRSQQANLLAEAKKLNDAQAPK; AGR-[BM2]-DQSQRANLLAEAKKLNDAQAPK; AGR-[BM2]-DQSQQANLLAEAKKLNDAQAPK; AGR-[BM2]-DPSQRANLLAEAKKLNDAQAPK; AGR-[BM2]-DRSQSANLLAEAKKLNDAQAPK; AGG-[BM2]-DPSQSANLLAEAKKLNDAQAPK; SGG-[BM2]-DPSQSANLLAEAKKLNDAQAPK; AGR-[BM2]-DRSQRANLLAEAKKLNDAQAPK; AGG-[BM2]-DSSQSANLLAEAKKLNDAQAPK; and AGG-[BM2]-DPSQNANLLAEAKKLNDAQAPK.

[0433] 18. A.beta. peptide binding polypeptide according to any one of items 1-17, wherein said linker is arranged between said first moiety and said second moiety.

[0434] 19. A.beta. peptide binding polypeptide according to item 18, wherein said linker is a flexible linker comprising at least one amino acid residue selected from the group consisting of glycine, serine and threonine.

[0435] 20. A.beta. peptide binding polypeptide according to item 19, wherein said linker has a general formula selected from

[0436] (G.sub.nS.sub.m).sub.p and (S.sub.nG.sub.m).sub.p,

[0437] wherein, independently,

[0438] n=1-7,

[0439] m=0-7,

[0440] n+m 8 and

[0441] p=1-10.

[0442] 21. A.beta. peptide binding polypeptide according to item 20, wherein n=1-5.

[0443] 22. A.beta. peptide binding polypeptide according to any one of items 20-21, wherein m=0-5.

[0444] 23. A.beta. peptide binding polypeptide according to any one of items 20-22, wherein p=1-5.

[0445] 24. A.beta. peptide binding polypeptide according to any one of items 20-23, wherein n=4, m=1 and p=2-3.

[0446] 25. A.beta. peptide binding polypeptide according to item 24, wherein said linker is selected from (S.sub.4G).sub.2 and (S.sub.4G).sub.3.

[0447] 26. A.beta. peptide binding polypeptide according to item 25, wherein said linker is (S.sub.4G).sub.2.

[0448] 27. A.beta. peptide binding polypeptide according to item 25, wherein said linker is (S.sub.4G).sub.3.

[0449] 28. A.beta. peptide binding polypeptide according to item 18, wherein said linker comprises an amino acid sequence selected from the group consisting of VEVDNKFNKEMAS, VDNKFNKEMAS, VEVDNKFNKE, VDNKFNKE, AEAKYAKE, ADNNFNK, ADNKFNK, ADAQQNNFNK, AQHDE, VDNKFNK, AEAKYAK, VDAKYAK, ADAKYAK.

[0450] 29. A.beta. peptide binding polypeptide according to any one of items 20-28, wherein said linker further comprises 1-5 additional amino acid residues at the N- or C-terminal end of said linker, such as 1-4 additional amino acid residues, such as 1-3 additional amino acid residues, such as 3 additional amino acid residues.

[0451] 30. A.beta. peptide binding polypeptide according to item 29, wherein said additional amino acid residues are selected from the group consisting of AS, MAS and RAS.

[0452] 31. A.beta. peptide binding polypeptide according to any preceding item, comprising a first moiety as defined in item 12 and a second moiety as defined in item 13.

[0453] 32. A.beta. peptide binding polypeptide according any preceding item, comprising a first moiety as defined in item 16 and a second moiety as defined in item 17.

[0454] 33. A.beta. peptide binding polypeptide according to any preceding item, wherein [0455] sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:1-106 and 118-553, and [0456] sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:1-17, 19-106 and 118-553 or to amino acid residues 69-90 in SEQ ID NO:18.

[0457] 34. A.beta. peptide binding polypeptide according to item 33, wherein [0458] sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159, and [0459] sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159 or to amino acid residues 69-90 in SEQ ID NO:18.

[0460] 35. A.beta. peptide binding polypeptide according to item 34, wherein [0461] sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159, and [0462] sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159 or to amino acid residues 69-90 in SEQ ID NO:18.

[0463] 36. A.beta. peptide binding polypeptide according to item 35, wherein [0464] sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:18, 70 and 95, and [0465] sequence i) of BM2 corresponds to any one of amino acid residues 64-85 in SEQ ID NO:70 and 95 or to amino acid residues 69-90 in SEQ ID NO:18.

[0466] 37. A.beta. peptide binding polypeptide according to item 36, wherein [0467] sequence i) of BM1 corresponds to amino acid residues 4-25 in SEQ ID NO:95 and [0468] sequence i) of BM2 corresponds to amino acid residues 64-85 in SEQ ID NO:95.

[0469] 38. A.beta. peptide binding polypeptide according to any preceding item, wherein [0470] the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:1-106 and 118-553, and [0471] the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:1-17, 19-106 and 118-553 or amino acid residues 66-90 in SEQ ID NO:18.

[0472] 39. A.beta. peptide binding polypeptide according to item 38, wherein [0473] the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159, and [0474] the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159 or amino acid residues 66-90 in SEQ ID NO:18.

[0475] 40. A.beta. peptide binding polypeptide according to item 39, wherein [0476] the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159, and [0477] the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159 or amino acid residues 66-90 in SEQ ID NO:18.

[0478] 41. A.beta. peptide binding polypeptide according to item 40, wherein [0479] the first moiety comprises amino acid residues 1-25 in any one of SEQ ID NO:18, 70 and 95, and [0480] the second moiety comprises amino acid residues 61-85 in any one of SEQ ID NO:70 and 95 or amino acid residues 66-90 in SEQ ID NO:18.

[0481] 42. A.beta. peptide binding polypeptide according to item 41, wherein [0482] the first moiety comprises amino acid residues 1-25 in SEQ ID NO:95, and [0483] the second moiety comprises amino acid residues 61-85 in SEQ ID NO:95.

[0484] 43. A.beta. peptide binding polypeptide according to any one of items 9-14, wherein [0485] sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:1-106 and 118-553, and [0486] sequence iii) in Bmod of the second moiety corresponds to amino acid residues 64-107 in any one of SEQ ID NO:1-17, 19-106 and 118-553 or amino acid residues 69-112 in SEQ ID NO:18.

[0487] 44. A.beta. peptide binding polypeptide according to item 43, wherein [0488] sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159, and [0489] sequence iii) in Bmod of the second moiety corresponds to amino acid residues 64-107 in any one of SEQ ID NO:1, 5, 9, 13, 14, 16, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159 or amino acid residues 69-112 in SEQ ID NO:18.

[0490] 45. A.beta. peptide binding polypeptide according to item 44, wherein [0491] sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159, and [0492] sequence iii) in Bmod of the second moiety corresponds to amino acid residues 64-107 in any one of SEQ ID NO:28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159 or amino acid residues 69-112 in SEQ ID NO:18.

[0493] 46. A.beta. peptide binding polypeptide according to item 45, wherein [0494] sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:18, 70 and 95, and [0495] sequence iii) in Bmod of the second moiety corresponds to amino acid residues 64-107 in any one of SEQ ID NO:70 and 95 or amino acid residues 69-112 in SEQ ID NO:18.

[0496] 47. A.beta. peptide binding polypeptide according to item 46, wherein [0497] sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in SEQ ID NO:95, and [0498] sequence iii) in Bmod of the second moiety corresponds to amino acid residues 64-107 in SEQ ID NO:95.

[0499] 48. A.beta. peptide binding polypeptide according to any one of items 33-47, wherein [0500] the first moiety comprises an amino acid sequence corresponding to amino acid residues 4-25, 1-25, 4-47 or 1-47 from any one of SEQ ID NO:1-106 and 118-553; and [0501] the second moiety comprises an amino acid sequence corresponding to amino acid residues 64-85, 61-85, 64-107 or 61-107 from any one of SEQ ID NO:1-17, 19-106 and 118-553 or to amino acid residues 69-90, 66-90, 69-112 or 66-112 from SEQ ID NO:18;

[0502] wherein both said amino acid sequences comprised in each of the first and second moieties are from the same SEQ ID NO.

[0503] 49. A.beta. peptide binding polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-106 and 118-553; such as from the group consisting of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159; such as from the group consisting of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159, such as from the group consisting of SEQ ID NO 18, 70 and 95.

[0504] 50. A.beta. peptide binding polypeptide according to item 49, comprising the amino acid sequence SEQ ID NO:95.

[0505] 51. A.beta. peptide binding polypeptide according to any preceding item, which is capable of binding to A.beta. peptide such that the K.sub.D value of the interaction is at most 1.times.10.sup.-7 M, such as at most 1.times.10.sup.-8 M, such as at most 1.times.10.sup.-9 M, such as at most 1.times.10.sup.-10 M.

[0506] 52. A.beta. peptide binding polypeptide, which constitutes a fragment of a polypeptide according to any preceding item, which fragment retains binding affinity for an A.beta. peptide.

[0507] 53. A.beta. peptide binding polypeptide according to any preceding item, which comprises at least one additional amino acid residue at at least one of the N terminus and the C terminus.

[0508] 54. A.beta. peptide binding polypeptide according to item 53, which comprises additional amino acid residues at both the N terminus and the C terminus.

[0509] 55. A.beta. peptide binding polypeptide according any one of items 53-54, wherein said at least one additional amino acid residue improves or simplifies production, purification, stabilization in vivo or in vitro, coupling or detection of the polypeptide.

[0510] 56. Fusion protein or conjugate, comprising [0511] a first part consisting of an A.beta. peptide binding polypeptide according to any preceding item; and [0512] a second part consisting of a polypeptide having a desired biological activity.

[0513] 57. Fusion protein or conjugate according to item 56, wherein said desired biological activity is a therapeutic activity.

[0514] 58. Fusion protein or conjugate according to item 56 or 57, wherein said desired biological activity is a binding activity.

[0515] 59. Fusion protein or conjugate according to item 58, wherein said binding activity of said second part is binding to A.beta. peptide.

[0516] 60. Fusion protein or conjugate according to item 58, wherein said binding activity is an albumin binding activity, which increases the in vivo half-life of the fusion protein or conjugate.

[0517] 61. Fusion protein or conjugate according to item 60, wherein said second part comprises the albumin binding domain of streptococcal protein G or a derivative thereof, such as comprising the amino acid sequence SEQ ID NO:107, SEQ ID NO:117 or a derivative thereof.

[0518] 62. Fusion protein or conjugate according to item 58 or 59, wherein said binding activity acts to block a biological activity.

[0519] 63. Fusion protein or conjugate according to item 58 or 59, wherein said binding activity acts to stimulate a biological activity.

[0520] 64. Fusion protein or conjugate according to item 58, wherein said binding activity is binding to a target selected from the group consisting of Tau, apolipoprotein E (ApoE), beta-secretase 1 (BACE1), gamma-secretase, transferrin receptor (TfR), complement factor C1s, presenilin 1, presenilin 2, nicastrin, alpha-synuclein and Bri.

[0521] 65. Fusion protein or conjugate according to item 56, wherein said desired biological activity is an enzymatic activity.

[0522] 66. Fusion protein or conjugate according to item 57, wherein the second part is a therapeutically active polypeptide.

[0523] 67. Fusion protein or conjugate according to any one of items 56-57 and 65-66, wherein the second part is selected from the group consisting of human endogenous enzymes, hormones, growth factors, chemokines, cytokines and lymphokines.

[0524] 68. Fusion protein or conjugate according to any one of items 56-57 and 65-66, wherein the second part is selected from the group consisting of antibodies and antigen binding fragments thereof.

[0525] 69. Fusion protein or conjugate according to item 68, wherein said antibody or antigen binding fragment thereof is selected from the group consisting of full-length antibodies, Fab fragments, Fab' fragments, F(ab').sub.2 fragments, Fc fragments, Fv fragments, single chain Fv fragments, (scFv).sub.2 and domain antibodies.

[0526] 70. Fusion protein or conjugate according to item 68 or 69, wherein said antibody or antigen binding fragment thereof has an affinity for a target selected from the group consisting of Tau, apolipoprotein E (ApoE), beta-secretase 1 (BACE1), gamma-secretase, transferrin receptor (TfR), complement factor C1s, presenilin 1, presenilin 2, nicastrin, alpha-synuclein and Bri.

[0527] 71. Fusion protein or conjugate according to any one of items 56-70, wherein the second part mediates transport of the fusion protein or conjugate to the cerebrospinal fluid or brain, for example being selected from the group consisting of transferrin, ghrelin, insulin and leptin.

[0528] 72. A.beta. peptide binding polypeptide, fusion protein or conjugate according to any preceding item, further comprising a label.

[0529] 73. A.beta. peptide binding polypeptide, fusion protein or conjugate according to item 72, wherein said label is selected from fluorescent dyes and metals, chromophoric dyes, chemiluminescent compounds and bioluminescent proteins, enzymes, radionuclides and radioactive particles.

[0530] 74. A.beta. peptide binding polypeptide, fusion protein or conjugate according to any preceding item, comprising a chelating environment provided by a polyaminopolycarboxylate chelator conjugated to the A.beta. peptide binding polypeptide via a thiol group of a cysteine residue or an amine group of a lysine residue.

[0531] 75. A polynucleotide encoding a polypeptide according to any one of items 1-71.

[0532] 76. Expression vector comprising a polynucleotide according to item 75.

[0533] 77. Host cell comprising an expression vector according to item 76.

[0534] 78. Method of producing a polypeptide according to any one of items 1-71, comprising [0535] culturing a host cell according to item 77 under conditions permissive of expression of said polypeptide from said expression vector, and [0536] isolating said polypeptide.

[0537] 79. Composition comprising an A.beta. peptide binding polypeptide, fusion protein or conjugate according to any one of items 1-74 and at least one pharmaceutically acceptable excipient or carrier.

[0538] 80. Composition according to item 79, further comprising at least one additional active agent.

[0539] 81. Composition according to item 80, wherein said additional active agent is selected from the group consisting of inhibitors of neurotransmitter degradation, neurotransmitters, acetylcholinesterase inhibitors, NMDA receptor antagonists, TNF inhibitors, antihistamines, anti-viral agents, alpha-secretase activators, inhibitors of beta- or gamma-secretase, inhibitors of .alpha.-synuclein aggregation, inhibitors of tau aggregation, calcium channel blockers, compounds effective against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair such as pirenzepin and metabolites, attractants for A.beta. clearing/depleting cellular components, inhibitors of N-terminal truncated A.beta. including pyroglutamated A.beta..sub.3-42, anti-inflammatory molecules, atypical antipsychotics such as clozapine, ziprasidone, risperidone, aripiprazole and olanzapine, cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil and galantamine, M1 agonists and other drugs including any amyloid or tau modifying drug and nutritive supplements such as vitamin B12, cysteine, acetylcholine precursor, lecithin, choline, Ginkgo biloba, acetyl-L-carnitine, idebenone, propentofylline, and xanthine derivatives.

[0540] 82. Composition according to item 81, wherein said additional active agent is selected from the group consisting of acetylcholinesterase inhibitors, NMDA receptor antagonists, TNF inhibitors, antihistamines and anti-viral agents.

[0541] 83. A.beta. peptide binding polypeptide, fusion protein or conjugate according to any one of items 1-74 or composition according to any one of items 80-82 for administration via a route selected from the group consisting of oral, intravenous, intraperitoneal, subcutaneous, intrathecal (e.g. via the Ommaya reservoir), pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual or suppository administration, such as selected from the group consisting of oral, intrathecal, intravenous and intranasal administration.

[0542] 84. A.beta. peptide binding polypeptide, fusion protein or conjugate according to any one of items 1-74 or a composition according to any one of items 80-82 for use as a medicament, as a diagnostic agent or as a prognostic agent.

[0543] 85. A.beta. peptide binding polypeptide, fusion protein, conjugate or composition for use as a medicament according to item 84, whereby said polypeptide, fusion protein, conjugate or composition reduces the amount of A.beta. peptide in blood.

[0544] 86. A.beta. peptide binding polypeptide, fusion protein, conjugate or composition for use as a medicament according to item 84, whereby said polypeptide, fusion protein, conjugate or composition slows down, stops or reverses an equilibrium between A.beta. monomers and A.beta. aggregates.

[0545] 87. A.beta. peptide binding polypeptide, fusion protein, conjugate or composition for use as a medicament according to item 84, whereby said polypeptide, fusion protein, conjugate or composition prevents or reverses A.beta. aggregate formation.

[0546] 88. A.beta. peptide binding polypeptide, fusion protein, conjugate or composition for use according to any one of items 84-87 in the treatment, diagnosis or prognosis of an A.beta. peptide associated condition, for example selected from the group consisting of amyloidosis, which refers to a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders or conditions characterized by a loss of cognitive memory capacity such as, for example, Alzheimer's disease (AD), mild cognitive impairment (MCI), Lewybody dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), the Guam Parkinson-dementia complex; as well as other diseases which are based on or associated with amyloid-like proteins such as cerebral amyloid angiopathy, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), inclusion-body myositis (IBM), type II diabetes, and senile cardiac amyloidosis; and various eye diseases including glaucoma, macular degeneration, drusen-related optic neuropathy, and cataract due to beta-amyloid deposition.

[0547] 89. A.beta. peptide binding polypeptide, fusion protein, conjugate or composition for use according to item 88, wherein the A.beta. peptide associated condition is Alzheimer's disease.

[0548] 90. Method for detecting an A.beta. peptide in a sample, comprising [0549] providing a sample suspected to contain A.beta. peptide, [0550] contacting said sample with an A.beta. peptide binding polypeptide, fusion protein or conjugate according to any one of items 1-74 or a composition according to any one of items 80-82, and [0551] detecting binding of the A.beta. peptide binding polypeptide, fusion protein, conjugate or composition,

[0552] wherein detection of binding indicates the presence of A.beta. peptide in the sample.

[0553] 91. Method for determining the presence of A.beta. peptide in a subject, the method comprising the steps: [0554] contacting the subject, or a sample isolated from the subject, with an A.beta. peptide binding polypeptide, fusion protein or conjugate according to any one of items 1-74 or a composition according to any one of items 80-82, and [0555] obtaining a value corresponding to the amount of A.beta. peptide binding polypeptide, fusion protein, conjugate or composition that has bound in said subject or to said sample.

[0556] 92. Method according to item 91, further comprising a step of comparing said value to a reference.

[0557] 93. Method according to item 91 or 92, wherein said subject is a mammalian subject, such as a human subject.

[0558] 94. Method according to any one of items 91-93, wherein the sample is a biological fluid sample, such as a sample selected form the group consisting of a whole blood sample, a plasma sample and a serum sample.

[0559] 95. Method according to any one of items 91-94, wherein the sample is a tissue sample.

[0560] 96. Method according to any one of items 91-95, performed in vivo.

[0561] 97. Method according to any one of items 91-95, performed in vitro.

[0562] 98. Method of treatment of an A.beta. peptide associated condition, comprising administering, to a subject in need thereof, an effective amount of an A.beta. peptide binding polypeptide, fusion protein or conjugate according to any one of items 1-74 or a composition according to any one of items 80-82.

[0563] 99. Method according to item 98, wherein said A.beta. peptide associated condition is selected from the group consisting of amyloidosis, which refers to a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders or conditions characterized by a loss of cognitive memory capacity such as, for example, Alzheimer's disease (AD), mild cognitive impairment (MCI), Lewybody dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), the Guam Parkinson-dementia complex; as well as other diseases which are based on or associated with amyloid-like proteins such as cerebral amyloid angiopathy, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), inclusion-body myositis (IBM), type II diabetes, and senile cardiac amyloidosis; and various eye diseases including glaucoma, macular degeneration, drusen-related optic neuropathy, and cataract due to beta-amyloid deposition.

[0564] 100. Method according to item 99, wherein said A.beta. peptide associated condition is Alzheimer's disease.

[0565] 101. Affinity matrix comprising an A.beta. peptide binding polypeptide, fusion protein or conjugate according to any one of items 1-74.

[0566] 102. Method of separation of A.beta. peptide present in a sample from other constituents in the sample, comprising a step of affinity separation, in which step an A.beta. peptide binding polypeptide according to any one of items 1-74 is used.

[0567] 103. Method according to item 102, comprising the steps: [0568] applying the sample to an affinity matrix according to item 101 under conditions permissive for binding of A.beta. peptide to the affinity matrix; [0569] washing the affinity matrix for removal of substances not bound thereto; and [0570] eluting the bound A.beta. peptide from the affinity matrix, thus obtaining an A.beta. peptide fraction with an enriched A.beta. peptide content; and [0571] recovering said A.beta. peptide fraction.

[0572] 104. Method according to item 102, comprising the steps: [0573] applying the sample to an affinity matrix according to item 101 under conditions permissive for binding of A.beta. peptide to the affinity matrix; [0574] washing the affinity matrix for recovery of substances not bound thereto, thus obtaining a depleted fraction with a substantially reduced A.beta. peptide content; and [0575] recovering said depleted fraction.

[0576] 105. Method for reducing the content of A.beta. peptide in a portion of a body fluid of a human, comprising the steps: [0577] providing a portion of a body fluid from a human; [0578] applying the portion of a body fluid to an affinity matrix according to item 101 under conditions permissive for binding of A.beta. peptide to the affinity matrix, thereby causing a reduction of the content of A.beta. peptide in the portion of body fluid; and [0579] returning at least a part of said portion of body fluid to said human.

[0580] 106. Method according to item 105, wherein said body fluid is whole blood.

[0581] 107. Method according to item 105, wherein said body fluid is plasma.

[0582] 108. Method according item 105, wherein said body fluid is serum.

[0583] 109. Method according to any one of items 105-108, wherein said sample of a body fluid is obtained from a subject suffering from an A.beta. peptide associated condition is selected from the group consisting of amyloidosis, which refers to a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders or conditions characterized by a loss of cognitive memory capacity such as, for example, Alzheimer's disease (AD), mild cognitive impairment (MCI), Lewybody dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), the Guam Parkinson-dementia complex; as well as other diseases which are based on or associated with amyloid-like proteins such as cerebral amyloid angiopathy, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), inclusion-body myositis (IBM), type II diabetes, and senile cardiac amyloidosis; and various eye diseases including glaucoma, macular degeneration, drusen-related optic neuropathy, and cataract due to beta-amyloid deposition.

Sequence CWU 1

1

5571107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 1Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 2107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 2Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 3107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 3Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 4107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 4Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 5107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 5Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 6107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 6Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 7107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 7Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Arg Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 8107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 8Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 9107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 9Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 10107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 10Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 11107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 11Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 12107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 12Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 13107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 13Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 14107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 14Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 15107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 15Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Ile Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 16107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 16Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 17107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 17Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 18112PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 18Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala 50 55 60 Ser Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln 65 70 75 80 Leu Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Gln Ser Gln Arg Ala 85 90 95 Asn Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 110 19107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 19Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 20107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 20Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu

Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 21107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 21Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 22107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 22Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 23107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 23Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 24107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 24Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 25107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 25Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 26107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 26Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 27107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 27Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 28107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 28Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 29107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 29Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 30107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 30Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 31107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 31Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Ile Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 32107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 32Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 33107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 33Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 34107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 34Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Thr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 35107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 35Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 36107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 36Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 37107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 37Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 38107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 38Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 39107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 39Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu

50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 40107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 40Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 41107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 41Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 42107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 42Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 43107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 43Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Phe Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 44107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 44Ala Gly Gly Glu Gln Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 45107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 45Ala Gly Gly Glu Tyr Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 46107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 46Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Ile Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 47107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 47Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 48107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 48Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 49107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 49Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 50107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 50Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 51107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 51Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 52107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 52Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 53107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 53Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 54107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 54Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 55107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 55Ala Gly Arg Glu Arg Val Tyr Ile Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 56107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 56Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 57107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 57Ala Gly Arg Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 58107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 58Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85

90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 59107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 59Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 60107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 60Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 61107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 61Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 62107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 62Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 63107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 63Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 64107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 64Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 65107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 65Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 66107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 66Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 67107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 67Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 68107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 68Ala Gly Arg Glu Arg Val Tyr Ile Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 69107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 69Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 70107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 70Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 71107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 71Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 72107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 72Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 73107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 73Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 74107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 74Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 75107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 75Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 76107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 76Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 77107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 77Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 78107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 78Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5

10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 79107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 79Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 80107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 80Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 81107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 81Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 82107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 82Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 83107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 83Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ser Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 84107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 84Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Lys 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 85107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 85Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 86107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 86Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 87107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 87Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 88107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 88Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 89107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 89Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 90107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 90Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 91107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 91Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 92107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 92Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 93107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 93Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 94107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 94Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 95107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 95Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 96107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 96Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 97107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 97Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45

Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 98107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 98Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 99107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 99Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 100107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 100Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 101107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 101Ala Gly Arg Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 102107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 102Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 103107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 103Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 104107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 104Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 105107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 105Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 106107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 106Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 10746PRTARTIFICIAL SEQUENCEEngineered albumin binding domain 107Leu Ala Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly 1 5 10 15 Val Ser Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu 20 25 30 Gly Val Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro 35 40 45 10858PRTARTIFICIAL SEQUENCEEngineered Taq binding polypeptide 108Val Asp Asn Lys Phe Asn Lys Glu Leu Gly Trp Ala Thr Trp Glu Ile 1 5 10 15 Phe Asn Leu Pro Asn Leu Asn Gly Val Gln Val Lys Ala Phe Ile Asp 20 25 30 Ser Leu Arg Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 35 40 45 Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 50 55 10942PRTHOMO SAPIENS 109Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 20 25 30 Gly Leu Met Val Gly Gly Val Val Ile Ala 35 40 11040PRTHOMO SAPIENS 110Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 20 25 30 Gly Leu Met Val Gly Gly Val Val 35 40 11158PRTARTIFICIAL SEQUENCEEngineered Abeta binding polypeptide 111Val Asp Asn Lys Phe Asn Lys Glu Met Ala Ser Ala Gly Gly Glu Ile 1 5 10 15 Val Tyr Leu Pro Asn Leu Asn Pro Asp Gln Leu Cys Ala Phe Ile His 20 25 30 Ser Leu His Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 35 40 45 Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 50 55 112118PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 112Val Asp Asn Lys Phe Asn Lys Glu Met Ala Ser Ala Gly Gly Glu Ile 1 5 10 15 Val Tyr Leu Pro Asn Leu Asn Pro Asp Gln Leu Cys Ala Phe Ile His 20 25 30 Ser Leu His Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 35 40 45 Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Val Glu Val Asp Asn Lys 50 55 60 Phe Asn Lys Glu Met Ala Ser Ala Gly Gly Glu Ile Val Tyr Leu Pro 65 70 75 80 Asn Leu Asn Pro Asp Gln Leu Cys Ala Phe Ile His Ser Leu His Asp 85 90 95 Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala Lys Lys Leu Asn 100 105 110 Asp Ala Gln Ala Pro Lys 115 113105PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding dimer polypeptide 113Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Pro Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile His Ser Leu His Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Ser 35 40 45 Ser Ser Gly Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu Ile Val 50 55 60 Tyr Leu Pro Asn Leu Asn Pro Asp Gln Leu Cys Ala Phe Ile His Ser 65 70 75 80 Leu His Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala Lys 85 90 95 Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 114201PRTARTIFICIAL SEQUENCEEngineered albumin binding protein 114Lys Leu Leu Asp Ala Leu Ala Lys Ala Lys Ala Asp Ala Leu Lys Glu 1 5 10 15 Phe Asn Lys Tyr Gly Val Ser Asp Tyr Tyr Lys Asn Leu Ile Asn Asn 20 25 30 Ala Lys Thr Val Glu Gly Val Lys Asp Leu Gln Ala Gln Val Val Glu 35 40 45 Ser Ala Lys Lys Ala Arg Ile Ser Glu Ala Thr Asp Gly Leu Ser Asp 50 55 60 Phe Leu Lys Ser Gln Thr Pro Ala Glu Asp Thr Val Lys Ser Ile Glu 65 70 75 80 Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly 85 90 95 Val Ser Asp Tyr His Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu 100 105 110 Gly Val Lys Asp Leu Gln Ala Gln Val Val Glu Ser Ala Lys Lys Ala 115 120 125 Arg Ile Ser Glu Ala Thr Asp Gly Leu Ser Asp Phe Leu Lys Ser Gln 130 135 140 Thr Pro Ala Glu Asp Thr Val Lys Ser Ile Glu Leu Ala Glu Ala Lys 145 150 155 160 Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp Tyr Tyr 165 170 175 Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys Ala Leu 180 185 190 Ile Asp Glu Ile Leu Ala Ala Leu Pro 195 200 115164PRTARTIFICIAL SEQUENCEAbeta binding dimer fused to albumin binding domain 115Met Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln 1 5 10 15 Leu Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala 20 25 30 Asn Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala 35 40 45 Ser Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly 50 55 60 Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe 65 70 75 80 Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala 85 90 95 Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Gly Ala Pro Gly 100 105 110 Gly Gly Gly Ser Thr Ser Leu Ala Glu Ala Lys Glu Ala Ala Asn Ala 115 120 125 Glu Leu Asp Ser Tyr Gly Val Ser Asp Phe Tyr Lys Arg Leu Ile Asp 130 135 140 Lys Ala Lys Thr Val Glu Gly Val Glu Ala Leu Lys Asp Ala Ile Leu 145 150 155 160 Ala Ala Leu Pro 116172PRTARTIFICIAL SEQUENCETaq binding dimer fused to albumin binding domain 116Met Gly Ser Ser Leu Gln Val Asp Asn Lys Phe Asn Lys Glu Leu Gly 1 5 10 15 Trp Ala Thr Trp Glu Ile Phe Asn Leu Pro Asn Leu Asn Gly Val Gln 20 25 30 Val Lys Ala Phe Ile Asp Ser Leu Arg Asp Asp Pro Ser Gln Ser Ala 35 40 45 Asn Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 50 55 60 Val Asp Asn Lys Phe Asn Lys Glu Leu Gly Trp Ala Thr Trp Glu Ile 65 70 75 80 Phe Asn Leu Pro Asn Leu Asn Gly Val Gln Val Lys Ala Phe Ile Asp 85 90 95 Ser Leu Arg Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 100 105 110 Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Val Asp Gly Ser Leu Ala 115 120 125 Glu Ala Lys Glu Ala Ala Asn Ala Glu Leu Asp Ser Tyr Gly Val Ser 130 135 140 Asp Phe Tyr Lys Arg Leu Ile Asp Lys Ala Lys Thr Val Glu Gly Val 145 150 155 160 Glu Ala Leu Lys Asp Ala Ile Leu Ala Ala Leu Pro 165 170 11746PRTStreptococcus sp. G148 117Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly 1 5 10 15 Val Ser Asp Tyr Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu 20 25 30 Gly Val Lys Ala Leu Ile Asp Glu Ile Leu Ala Ala Leu Pro 35 40 45 118107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 118Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5

10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 119107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 119Ala Gly Arg Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 120107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 120Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 121107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 121Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 122107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 122Ala Gly Arg Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 123107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 123Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 124107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 124Ala Gly Arg Glu Arg Val Tyr Ile Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 125107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 125Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 126107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 126Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 127107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 127Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 128107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 128Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 129107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 129Ala Gly Arg Glu Arg Val Tyr Ile Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 130107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 130Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Arg Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 131107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 131Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 132107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 132Ala Gly Arg Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 133107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 133Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 134107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 134Ala Gly Arg Glu Arg Val Tyr Ile Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 135107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 135Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 136107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 136Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 137107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 137Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85

90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 138107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 138Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 139107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 139Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 140107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 140Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 141107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 141Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Gln Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 142107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 142Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 143107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 143Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 144107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 144Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Ile Thr Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 145107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 145Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 146107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 146Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 147107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 147Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 148107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 148Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 149107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 149Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 150107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 150Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 151107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 151Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 152107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 152Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 153107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 153Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 154107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 154Ala Gly Arg Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 155107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 155Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 156107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 156Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 157107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 157Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly

Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 158107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 158Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 159107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 159Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 160107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 160Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Glu Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 161107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 161Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 162107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 162Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 163107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 163Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 164107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 164Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 165107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 165Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 166107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 166Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 167107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 167Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 168107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 168Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 169107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 169Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 170107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 170Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 171107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 171Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 172107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 172Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 173107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 173Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 174107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 174Ala Gly Gly Glu Met Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 175107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 175Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 176107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 176Ala Gly Gly Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 177107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 177Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile

Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 178107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 178Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 179107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 179Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 180107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 180Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 181107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 181Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 182107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 182Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 183107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 183Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 184107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 184Ala Gly Gly Glu Met Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 185107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 185Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 186107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 186Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 187107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 187Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 188107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 188Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 189107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 189Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 190107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 190Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 191107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 191Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 192107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 192Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 193107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 193Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 194107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 194Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 195107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 195Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 196107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 196Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu

Asn Asp Ala Gln Ala Pro Lys 100 105 197107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 197Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 198107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 198Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 199107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 199Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 200107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 200Ala Gly Gly Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 201107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 201Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 202107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 202Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 203107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 203Ala Gly Gly Glu Ile Val Tyr Leu Arg Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 204107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 204Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 205107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 205Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 206107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 206Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 207107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 207Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 208107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 208Ala Gly Arg Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 209107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 209Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 210107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 210Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 211107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 211Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 212107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 212Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Glu Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 213107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 213Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 214107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 214Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 215107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 215Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 216107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 216Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55

60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 217107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 217Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 218107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 218Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Gln Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 219107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 219Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 220107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 220Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 221107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 221Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 222107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 222Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 223107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 223Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 224107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 224Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 225107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 225Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 226107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 226Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 227107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 227Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 228107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 228Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 229107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 229Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 230107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 230Ala Gly Gly Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Glu Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 231107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 231Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 232107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 232Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 233107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 233Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 234107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 234Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 235107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 235Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 236107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 236Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn

20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 237107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 237Ala Gly Arg Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 238107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 238Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 239107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 239Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 240107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 240Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 241107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 241Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 242107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 242Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 243107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 243Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Gln Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 244107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 244Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Glu Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 245107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 245Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 246107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 246Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 247107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 247Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 248107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 248Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 249107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 249Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 250107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 250Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 251107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 251Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 252107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 252Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 253107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 253Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 254107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 254Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 255107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 255Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105

256107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 256Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 257107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 257Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 258107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 258Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 259107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 259Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 260107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 260Ala Gly Arg Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 261107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 261Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 262107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 262Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 263107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 263Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 264107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 264Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 265107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 265Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 266107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 266Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 267107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 267Ala Gly Gly Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 268107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 268Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 269107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 269Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 270107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 270Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 271107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 271Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 272107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 272Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 273107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 273Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 274107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 274Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 275107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 275Ala Gly Arg Glu Gln Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln

Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 276107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 276Ala Gly Arg Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 277107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 277Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 278107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 278Ala Gly Arg Glu Arg Val Tyr Ile Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 279107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 279Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 280107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 280Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 281107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 281Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 282107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 282Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 283107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 283Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Arg Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 284107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 284Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 285107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 285Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 286107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 286Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 287107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 287Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 288107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 288Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Ile Thr Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 289107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 289Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 290107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 290Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 291107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 291Ala Gly Arg Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 292107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 292Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 293107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 293Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 294107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 294Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 295107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 295Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn 20 25 30 Leu

Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 296107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 296Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 297107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 297Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 298107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 298Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Glu Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 299107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 299Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 300107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 300Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 301107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 301Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 302107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 302Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 303107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 303Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Tyr Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 304107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 304Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 305107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 305Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 306107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 306Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 307107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 307Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 308107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 308Ala Gly Arg Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 309107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 309Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 310107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 310Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 311107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 311Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 312107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 312Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 313107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 313Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 314107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 314Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 315107PRTARTIFICIAL SEQUENCEEngineered Abeta

peptide binding polypeptide 315Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 316107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 316Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 317107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 317Ala Gly Gly Glu Ile Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Glu Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 318107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 318Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 319107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 319Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 320107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 320Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 321107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 321Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 322107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 322Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 323107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 323Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 324107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 324Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 325107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 325Ala Gly Arg Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 326107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 326Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 327107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 327Ala Gly Arg Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 328107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 328Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 329107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 329Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 330107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 330Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 331107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 331Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 332107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 332Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 333107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 333Ala Gly Arg Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 334107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 334Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70

75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 335107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 335Ala Gly Gly Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 336107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 336Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 337107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 337Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 338107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 338Ala Gly Arg Glu Ile Val Tyr Ile Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 339107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 339Ala Gly Arg Glu Arg Val Tyr Ile Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 340107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 340Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 341107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 341Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 342107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 342Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 343107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 343Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 344107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 344Ala Gly Arg Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 345107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 345Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 346107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 346Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 347107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 347Ala Gly Arg Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 348107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 348Ala Gly Arg Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 349107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 349Ala Gly Gly Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Glu Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 350107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 350Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 351107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 351Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 352107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 352Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 353107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 353Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 354107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 354Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro

Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 355107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 355Ala Gly Arg Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 356107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 356Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 357107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 357Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 358107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 358Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 359107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 359Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 360107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 360Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Ile Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 361107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 361Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 362107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 362Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 363107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 363Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 364107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 364Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 365107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 365Ala Gly Gly Glu Ile Val Tyr Phe Arg Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 366107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 366Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 367107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 367Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 368107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 368Ala Gly Arg Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 369107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 369Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 370107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 370Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 371107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 371Ala Gly Gly Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Glu Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 372107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 372Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 373107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 373Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Gln Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 374107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 374Ala Gly Gly Glu

Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Asn Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 375107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 375Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Glu Ser Gln Asn Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 376107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 376Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 377107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 377Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 378107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 378Ala Gly Gly Glu Gln Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 379107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 379Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 380107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 380Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 381107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 381Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 382107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 382Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 383107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 383Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 384107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 384Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 385107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 385Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 386107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 386Ala Gly Gly Glu Ile Val Tyr Ile Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 387107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 387Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 388107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 388Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 389107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 389Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 390107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 390Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 391107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 391Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 392107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 392Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 393107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 393Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp

Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 394107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 394Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 395107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 395Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 396107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 396Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 397107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 397Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 398107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 398Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 399107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 399Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 400107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 400Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 401107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 401Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 402107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 402Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 403107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 403Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 404107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 404Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 405107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 405Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 406107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 406Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 407107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 407Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 408107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 408Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Ser Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 409107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 409Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 410107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 410Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Ser Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 411107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 411Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 412107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 412Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 413107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 413Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40

45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 414107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 414Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 415107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 415Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 416107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 416Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 417107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 417Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 418107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 418Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 419107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 419Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 420107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 420Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 421107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 421Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 422107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 422Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 423107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 423Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 424107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 424Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 425107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 425Ala Gly Gly Glu Gln Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 426107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 426Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 427107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 427Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 428107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 428Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 429107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 429Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 430107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 430Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Gln Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 431107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 431Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 432107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 432Ala Gly Gly Glu Ile Val Tyr Ile Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 433107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 433Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1

5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 434107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 434Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 435107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 435Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 436107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 436Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 437107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 437Ala Gly Gly Glu Gln Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 438107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 438Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 439107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 439Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Arg Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 440107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 440Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 441107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 441Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 442107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 442Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 443107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 443Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 444107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 444Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 445107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 445Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 446107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 446Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 447107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 447Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 448107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 448Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 449107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 449Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 450107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 450Ala Gly Gly Glu Gln Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 451107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 451Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Ile Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 452107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 452Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu

85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 453107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 453Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 454107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 454Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 455107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 455Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 456107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 456Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 457107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 457Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 458107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 458Ala Gly Gly Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 459107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 459Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 460107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 460Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 461107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 461Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 462107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 462Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 463107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 463Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 464107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 464Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 465107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 465Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 466107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 466Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Phe Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 467107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 467Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 468107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 468Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 469107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 469Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 470107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 470Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 471107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 471Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 472107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 472Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly

Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 473107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 473Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 474107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 474Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 475107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 475Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 476107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 476Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 477107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 477Ala Gly Gly Glu Arg Val Tyr Leu Arg Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 478107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 478Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 479107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 479Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 480107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 480Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 481107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 481Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Ser Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 482107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 482Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 483107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 483Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 484107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 484Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 485107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 485Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 486107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 486Ala Gly Gly Glu Tyr Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 487107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 487Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Phe Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 488107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 488Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 489107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 489Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 490107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 490Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Arg Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 491107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 491Ala Gly Arg Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 492107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 492Ala Gly Gly Glu Arg Val Tyr Leu Tyr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15

Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 493107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 493Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 494107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 494Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 495107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 495Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 496107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 496Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 497107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 497Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Ser Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 498107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 498Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 499107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 499Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Met Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 500107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 500Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 501107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 501Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 502107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 502Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 503107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 503Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 504107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 504Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 505107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 505Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Ser Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 506107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 506Ala Gly Gly Glu Arg Val Tyr Phe Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 507107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 507Ala Gly Gly Glu Gln Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 508107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 508Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 509107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 509Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 510107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 510Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 511107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 511Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys

Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 512107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 512Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 513107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 513Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 514107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 514Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Ile Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 515107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 515Ala Gly Gly Glu Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 516107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 516Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 517107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 517Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 518107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 518Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 519107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 519Ala Gly Gly Glu Arg Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 520107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 520Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 521107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 521Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 522107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 522Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 523107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 523Ala Gly Gly Glu Met Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 524107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 524Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 525107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 525Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 526107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 526Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 527107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 527Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 528107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 528Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Gln Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 529107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 529Ala Gly Gly Glu Gln Val Tyr Phe Thr Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 530107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 530Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 531107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 531Ala Gly Gly Glu Gln Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55

60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 532107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 532Ala Gly Gly Glu Ile His Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Gln Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 533107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 533Ala Gly Gly Glu Gln Val Tyr Phe Arg Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 534107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 534Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 535107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 535Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 536107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 536Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 537107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 537Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 538107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 538Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Glu Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 539107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 539Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 540107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 540Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Arg Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 541107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 541Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 542107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 542Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Ser Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 543107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 543Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 544107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 544Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Ile Glu Asp Asp Ser Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 545107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 545Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Leu Glu Asp Asp Arg Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 546107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 546Ala Gly Gly Glu Ile Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala His Gln Leu Cys Ala Phe Ile 65 70 75 80 Gln Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 547107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 547Ala Gly Gly Glu Arg Val Tyr Leu Thr Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Asn Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 548107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 548Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 549107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 549Ala Gly Gly Glu Ile Val Tyr Phe Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Gln Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Ser Ser Gln Arg Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 550107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 550Ala Gly Gly Glu Met Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Asn Ser Leu Glu Asp Asp Pro Ser Gln Gln Ala Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Arg Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Ile Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 100 105 551107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 551Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala

Asn 20 25 30 Leu Leu Ala Glu Ala Lys Lys Leu Ser Glu Ala Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 85 90 95 Ala Lys Lys Leu Ser Glu Ala Gln Ala Pro Lys 100 105 552107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 552Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ser Glu 20 25 30 Leu Leu Ser Glu Ala Lys Lys Leu Ser Glu Ser Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Ser Leu Glu Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu 85 90 95 Ala Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys 100 105 553107PRTARTIFICIAL SEQUENCEEngineered Abeta peptide binding polypeptide 553Ala Gly Gly Glu Arg Val Tyr Leu Pro Asn Leu Thr Ala Asp Gln Leu 1 5 10 15 Cys Ala Phe Ile Arg Lys Leu Glu Asp Asp Pro Ser Gln Ser Ser Glu 20 25 30 Leu Leu Ser Glu Ala Lys Lys Leu Ser Glu Ser Gln Ala Pro Ala Ser 35 40 45 Ser Ser Ser Gly Ser Ser Ser Ser Gly Arg Ala Ser Ala Gly Gly Glu 50 55 60 Arg Val Tyr Leu Pro Asn Leu Thr Ala Asp Gln Leu Cys Ala Phe Ile 65 70 75 80 Arg Lys Leu Glu Asp Asp Pro Ser Gln Ser Ser Glu Leu Leu Ser Glu 85 90 95 Ala Lys Lys Leu Ser Glu Ser Gln Ala Pro Lys 100 105 55458PRTARTIFICIAL SEQUENCEEngineered Abeta binding polypeptide 554Val Asp Asn Lys Phe Asn Lys Glu Gly Lys Gly Ala Pro Gly Glu Ile 1 5 10 15 His Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile Arg 20 25 30 Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 35 40 45 Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 50 55 55558PRTARTIFICIAL SEQUENCEEngineered Abeta binding polypeptide 555Val Asp Asn Lys Phe Asn Lys Glu Ile Glu Val Ala Thr Gly Glu Ile 1 5 10 15 Val Tyr Leu Pro Asn Leu Asn Ala Asp Gln Leu Cys Ala Phe Ile Asn 20 25 30 Ser Leu Glu Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 35 40 45 Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 50 55 556278DNAARTIFICIAL SEQUENCELibrary oligonucleotidemisc_feature(13)..(18)n is a, c, g, or tmisc_feature(22)..(27)n is a, c, g, or tmisc_feature(40)..(42)n is a, c, g, or tmisc_feature(61)..(63)n is a, c, g, or tmisc_feature(88)..(90)n is a, c, g, or tmisc_feature(193)..(195)n is a, c, g, or tmisc_feature(205)..(207)n is a, c, g, or tmisc_feature(220)..(222)n is a, c, g, or tmisc_feature(235)..(237)n is a, c, g, or tmisc_feature(241)..(243)n is a, c, g, or tmisc_feature(247)..(249)n is a, c, g, or tmisc_feature(259)..(261)n is a, c, g, or tmisc_feature(268)..(270)n is a, c, g, or t 556gcgggtgggg agnnnnnnta tnnnnnnaac ttaaacgcgn nncaactgtg tgccttcatc 60nnnagtttag aagatgaccc aagccaannn gctaacttgt tggcagaagc taaaaagcta 120aatgatgctc aggcgccggc gagcagcagc agcgggagca gcagcagcgg gcgcgcgagt 180gcgggtcgcg agnnngttta tttannnaac ttaaacgcgn nncaactgtg tgccnnnatc 240nnnagtnnng aagatgacnn nagccaannn gctaactt 278557278DNAARTIFICIAL SEQUENCELibrary oligonucleotidemisc_feature(7)..(9)n is a, c, g, or tmisc_feature(13)..(15)n is a, c, g, or tmisc_feature(22)..(27)n is a, c, g, or tmisc_feature(40)..(42)n is a, c, g, or tmisc_feature(61)..(63)n is a, c, g, or tmisc_feature(79)..(81)n is a, c, g, or tmisc_feature(88)..(90)n is a, c, g, or tmisc_feature(187)..(189)n is a, c, g, or tmisc_feature(193)..(195)n is a, c, g, or tmisc_feature(202)..(207)n is a, c, g, or tmisc_feature(220)..(222)n is a, c, g, or tmisc_feature(241)..(243)n is a, c, g, or tmisc_feature(259)..(261)n is a, c, g, or tmisc_feature(268)..(270)n is a, c, g, or t 557gcgggtnnng agnnngttta tnnnnnnaac ttaaacgcgn nncaactgtg tgccttcatc 60nnnagtttag aagatgacnn nagccaannn gctaacttgt tggcagaagc taaaaagcta 120aatgatgctc aggcgccggc gagcagcagc agcgggagca gcagcagcgg gcgcgcgagt 180gcgggtnnng agnnngttta tnnnnnnaac ttaaacgcgn nncaactgtg tgccttcatc 240nnnagtttag aagatgacnn nagccaannn gctaactt 278

Claims

1. An A.beta. peptide binding polypeptide, which comprises a first moiety comprising a first A.beta. peptide binding motif BM1, a second moiety comprising a second A.beta. peptide binding motif BM2, which motifs may be the same or different, and a linker, wherein each one of said binding motifs BM1 and BM2 consists of an amino acid sequence selected from i) EX.sub.2X.sub.3YX.sub.5X.sub.6NLX.sub.9A X.sub.11QLCAX.sub.16IX.sub.18X.sub.19X.sub.20 ED wherein, independently from each other, X.sub.2 is selected from I, M, Q, R, T and Y; X.sub.3 is selected from H and V; X.sub.5 is selected from F, I and L; X.sub.6 is selected from P and T; X.sub.9 is selected from N and T; X.sub.11 is selected from D and H; X.sub.16 is selected from F and I; X.sub.18 is selected from N, Q and R; X.sub.19 is selected from K and S; and X.sub.20 is selected from F, I, L and R; and ii) an amino acid sequence which has at least 95% identity to the sequence defined in i).

2. The A.beta. peptide binding polypeptide according to claim 1, wherein at least one of first and second moieties comprises a binding module amino acid sequence, Bmod, selected from iii) [BM]-DXaSQXbXcXdLLXe EAKKLXfXgXhQA PXi wherein BM is BM1 or BM2 as defined in claim 1, and, independently of each other, X.sub.a is selected from P, Q, R and S; X.sub.b is selected from N, Q, R and S; X.sub.c is selected from A and S; X.sub.d is selected from K, N and E; X.sub.e is selected from A, S and C; X.sub.f is selected from E, N and S; X.sub.g is selected from D, E and S; X.sub.h is selected from A and S; and X.sub.i is selected from no amino acid, A and K, and iv) an amino acid sequence which has at least 97% identity to a sequence defined in iii).

3. The A.beta. peptide binding polypeptide according to claim 2, wherein sequence iii) consists of the amino acid sequence [BM]-DXaSQXbAXdLLA EAKKLNDAQA PXi wherein BM is BM1 or BM2 as defined in claim 1, and, independently of each other, X.sub.a is selected from P, Q, R and S; X.sub.b is selected from N, Q, R and S; X.sub.d is selected from K and N; and X.sub.i is selected from no amino acid, A and K.

4. The A.beta. peptide binding polypeptide according to claim 1, wherein sequence i) of BM1 corresponds to amino acid residues 4-25 in any one of SEQ ID NO:1-106 and 118-553, and sequence i) of BM2 corresponds to amino acid residues 64-85 in any one of SEQ ID NO:1-17, 19-106 and 118-553 or to amino acid residues 69-90 in SEQ ID NO:18.

5. The A.beta. peptide binding polypeptide according to claim 4, wherein sequence i) of BM1 corresponds to amino acid residues 4-25 in SEQ ID NO:95 and sequence i) of BM2 corresponds to amino acid residues 64-85 in SEQ ID NO:95.

6. The A.beta. peptide binding polypeptide according to claim 2, wherein sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in any one of SEQ ID NO:1-106 and 118-553, and sequence iii) in Bmod of the second moiety corresponds to amino acid residues 64-107 in any one of SEQ ID NO:1-17, 19-106 and 118-553 or amino acid residues 69-112 in SEQ ID NO:18.

7. The A.beta. peptide binding polypeptide according to claim 6, wherein sequence iii) in Bmod of the first moiety corresponds to amino acid residues 4-47 in SEQ ID NO:95, and sequence iii) in Bmod of the second moiety corresponds to amino acid residues 64-107 in SEQ ID NO:95.

8. An A.beta. peptide binding polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-106 and 118-553.

9. The A.beta. peptide binding polypeptide according to claim 1, which is capable of binding to A.beta. peptide such that the KD value of the interaction is at most 1.times.10.sup.-7 M.

10. A Fusion protein or conjugate, comprising a first part consisting of an A.beta. peptide binding polypeptide according to claim 1; and a second part consisting of a polypeptide having a desired biological activity.

11. The Fusion protein or conjugate according to claim 10, wherein said desired biological activity is a binding activity.

12. The Fusion protein or conjugate according to claim 10, wherein the second part is selected from the group consisting of antibodies and antigen binding fragments thereof.

13. A Composition comprising an A.beta. peptide binding polypeptide, fusion protein or conjugate according to claim 1 and at least one pharmaceutically acceptable excipient or carrier.

14.-15. (canceled)

16. The A.beta. binding polypeptide of claim 8, comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, 5, 9, 13, 14, 16, 18, 20, 21, 25, 26, 28, 33, 35, 37, 40, 42, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 64, 65, 70, 72, 75, 78, 84, 89, 90, 95, 96, 97, 100, 104 and 118-159.

17. The A.beta. binding polypeptide of claim 8, comprising an amino acid sequence selected from the group consisting of SEQ ID NO:18, 28, 35, 49, 50, 51, 55, 59, 64, 65, 70, 72, 78, 84, 95 and 118-159.

18. The A.beta. binding polypeptide of claim 8, comprising an amino acid sequence selected from the group consisting of SEQ ID NO 18, 70 and 95.

19. The A.beta. binding polypeptide of claim 8, comprising an amino acid sequence selected from the group consisting of SEQ ID NO:95.

20. The fusion protein or conjugate according to claim 11, wherein said binding activity is binding to a target selected from the group consisting of Tau, apolipoprotein E (ApoE), beta-secretase 1 (BACE1), gamma-secretase, transferrin receptor (TfR), complement factor C1s, presenilin 1, presenilin 2, nicastrin, alpha-synuclein and Bri.

21. The composition of claim 13, further comprising at least one active agent, said active agent selected from the group consisting of inhibitors of neurotransmitter degradation, neurotransmitters, acetylcholinesterase inhibitors, NMDA receptor antagonists, TNF inhibitors, antihistamines, anti-viral agents, alpha-secretase activators, inhibitors of beta- or gamma-secretase, inhibitors of .alpha.-synuclein aggregation, inhibitors of tau aggregation, calcium channel blockers, compounds effective against oxidative stress, anti-apoptotic compounds, metal chelators, pirenzepin and metabolites, attractants for A.beta. clearing/depleting cellular components, inhibitors of N-terminal truncated A.beta. including pyroglutamated A.beta.3-42, anti-inflammatory molecules, clozapine, ziprasidone, risperidone, aripiprazole, olanzapine, tacrine, rivastigmine, donepezil, galantamine, amyloid or tau modifying drugs, vitamin B12, cysteine, acetylcholine precursor, lecithin, choline, Ginkgo biloba, acetyl-L-carnitine, idebenone, propentofylline, xanthine derivatives, and combinations thereof.

22. A method for the treatment of an A.beta. peptide associated condition, comprising administering to a subject in need thereof, an effective amount of an A.beta. peptide binding polypeptide according to claim 1, a fusion protein according to claim 10, or a composition according to claim 13.

23. The method of claim 22, wherein the A.beta. associated condition is selected from the group consisting of amyloidosis, secondary amyloidosis, age-related amyloidosis, Alzheimer's disease (AD), mild cognitive impairment (MCI), Lewybody dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), the Guam Parkinson-dementia complex; cerebral amyloid angiopathy, primary and secondary systemic amyloidosis, familial amyloid polyneuropathy 1, progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), inclusion-body myositis (IBM), type II diabetes, senile cardiac amyloidosis, glaucoma, macular degeneration, drusen-related optic neuropathy, and cataract due to beta-amyloid deposition.