Title of Invention	PEPTIDE COMPRISING LESS THAN 10 AMINO ACIDS AND CAPABLE OF SELF-AGGREGATING UNDER PHYSIOLOGICAL CONDITIONS
Abstract	ABSTRACT 1671/CHENP/20Q4 1 "PEPTIDE COMPRISING LESS THAN 10 AMINO ACIDS AND CAPABLE OF SELF-AGGREGATING UNDER PHYSIOLOGICAL CONDITIONS" This invention relates to a peptide comprising less than 10 amino acid residues, the peptide including an amino acid sequence as set forth in SEQ ID NO: 7 and a proline, wherein the peptide is capable of self-aggregating under physiological conditions.

Full Text

The present invention relates to peptides and antibodies directed thereagainst which can be used lo diagnose, prevent, and treat amyloid-associated diseases, such as Type 11 diabetes meilitus. Amyloid materia] deposition (also rcrerred to a-s amyloid plaque formation) is a central fearure of a varietv oi" unrelated Datholoeical conditions including Alzheimer's disease, pnon-relaled encephalopathies, type n diabetes meilitus, familial amyloidosis and light-chain amyloidosis. Amyloid materia! is composed of a dense network of rigid, nonbranchiiig proteinaceous fibrils of indefinite length that are about SO to 100 A in diameter, -Amyloid fibnls contain a core structure of polypeptide chains arranged in antiparallel 0-pIeated sheets lying with their long axes perpendicuiar to the long axis of the fibnl (Both et al, (1997) Nature 3S5:7S7-93; Glenner (1980) N. Eng. J. Med. 302:1233-92], Approximately inventory amyloid fibril proteins have been identified in-vivo and correlated with specific diseases. These proteins share little or no amino acid sequence homology, however the core structure of the amyloid fibrils is essentially the same. This common core structure of amyloid fibrils and the presence of common substances in amyloid deposits suggest that data characterizing a particular form of amyloid material may also be relevant to other forms of amyloid material and thus can be implemented in template design for the development of drugs against amyloid-associated diseases such as type n diabetes meUitus, Alzheimer's dementia or diseases and prion-retated encephalopathies. Furthermore, amyloid deposits do not appear to be inert in vivo, but rather are in a dynamic state of turnover and can even regress if the formation of fibrils is halted [Gillmore et al. (1997) Br. J. Haematol. 99:245-56]. Thus, therapies designed to inhibiting the production of amyloid polypeptides or inhibiting amyloidosis may be useful for treating amyloid associated diseases. j/t/iiDifion oj the production of amyloid polypeptides - Direct inhibition of the production of amyloid polypeptides may be accompiished, for example, through the use of antisense oligonucleotides such as against human islet amyloid polypepude messenger RNA (mRNA). In vitro, the addition of antisense oligonucleotides or the expression ofanlisense complementary DNA against islet amyloid polypeptidemRNA increased the insulin mRNA and protein content of cells, demonstrating the potential effectiveness of this approach [Kulkami el al. (1995) J. Endocrinol. 151:341-8; Noviais et al. (199S) Pancreas 17:182-6]. However, no experimental results demonstraling Ihe in vivo effectiveness of such antisense molecules have been demoastrated- Inhibition of ihe formation of amyloid fibrils - Amyloid, including islet amyloid, contains potential stabilizing or protective substances, such as serum amyloid P component, apolipoprotein E, and perlecan. Blocking their binding to developing amyloid fibrils could inhibit amyloidogenesis [Kahn et al, (1999) Diabetes 48:241-53], as could treatment with antibodies specific for cenain parts of an amyioidogenic protein [Solomon et ai. (1997) Proc. Natl. Aciid. Sci. USA 94:4109-12]. The following summarizes current attempts to engineer drugs having the capability of destabilizing amyloid structures. Destabilizing compounds - Heparin sulfate has been identified as a component of all amyloids and has also been implicated in the earliest stages of inflammatioB-assDciated amyloid induction. Kisilevsky and co-workers (Mat\iie Med. 1:143-148, 1995) described the use of low molecular weight anionic sulfonate or sulfate compounds that interfere with the interaction of heparin sulfate with the inflammation-associated amyloid precursor and the p peptide of Alzheimer's disease (AD). Heparin sulfate specifically influences the soluble amyloid precursor (SAA2) to adopt an increased p-sheet structure characteristic of the protein-folding partem of amyloids. These anionic sulfonate or sulfate compounds were shown to inhibit heparin accelerated Ap fibril formation and were able to disassemble preformed fibrils in vilro, as monitored by electron micrography. Moreover, these compounds substantially arrested murine splenic inflammation-associated amyloid progression in vivo in acute and chronic models. However, the most potent compound [i.e., poly- (vinylsulfonate)] showed acute toxicity. Similar toxicity has been observed with another compound, [DOX (Aiithrac;.c[inG 4"-iodo-4'-deoxy-doxorubicin), which has been observed to induce amyloid resorption in patients wiih inununoglobin light chain amyloidosis (AL) [Meriini et ai. (1995) Proc. Natl. Acad. Sci- USA]. Destabilizing antibodies - Ajiti-ji-amyloid monocional antibodies have been shown to be cfTeclive in dis^ggregat.ng \\ -amNioid plaques and preventing p-amyloid plaque formation :n vitro ("U.S, PaL No. 5,6$S,56I). However, no experimental results demonstrating Ihe in vivo effeciiver.L^ss of such antibodies have been demonstrated. Destabilizing peptides - The finding thjt the addition of synthetic peptides that disrupt the B-pleated sheets ("B-shcet breakers") dissociated fibrils and prevented amyloidosis [Soto et al. (1998) Nat. Med. 4:822-6] is particularly promising from a clinical point of view, [n brief, a penta-residue peptide inhibited amyloid beta-protein fibrillogenesis, disassembled preformed fibrils in vitro and prevents neuronal death induced by fibrils in cell culture. In addition, the beta-sheet breaker peptide significantly reduced amyloid bcla-protein deposition in vivo and completely blocked the formation of amyloid fibrils in a rat brain model of amyloidosis. Small molecules - The potential use of small molecules which bind the amyloid polypeptide, stabilizing the native fold of the protein has been attempted in the case of the transthyretin (TTR) protein [Peterson (1998) Proc. Natl. Acad. Sci. USA 95-.12965-12960; Oza (1999) Bioorg. Med. Chem. Lett. 9:1-6], Thus far, it has been demonstrated that molecules such as thyroxine and flufenamic acid are capable of preventing Ihe conformation change, leading to amyloid formation. However, ihe use of the compounds in animal models has not been proved yet and might be compromised due to the presence in blood or proteins, other than TTR, capable of binding these ligands. Antioxidants - Another proposed therapy has been the intake of antioxidants in order to avoid oxidative stress and maintain amyloid proteins in their reduced state (i.e., monomers and dimers). The use of sulfite was shown to lead to more stable monomers of the TTR both in vitro and in vivo [.Altland (1999) Neurogenetics 2:183-188]. However, a complete characterization of the antioxidant effect is still not available and the inlerpretation of results concerning possible iherapeutic strategies remains difficult. While reducing the present invenlion lo practice, the present inventors have demonstrated that contrary to the teachings of U.S. Pat. No. 6,359,112 to Kapumiotu, peptide aggregation into amyloid fibrils is governed by aromatic interactions. Such findings enable to efficiently and accurately design peptides, which can be used to diagnose and treat ainyloid-associaieJ diseases. SUMM.AJ^Y OF THE IN\'ENTION According to one aspect of ;he present invention there is provided a peptide comprising a£ least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence as set forth in SEQ ID NO: 7. According to further features in preferred embodiments of the invention described below the amino acid sequence funher includes a polar uncharged amino acid selected from the group consisting of serine, threonine, asparagine, glulamine and natural derivatives thereof According !o still further features in the descnbed preferred embodiments the amino acid sequence funher includes at least one positively charged amino acid and at least one negatively charged amino acid. According to still further features in the described preferred embodiments the at least one positively charged amino acid is selected from the group consisting of lysine, arginine and natural and synthetic derivatives thereof. According to still further features in the described preferred embodiments the at least one negatively charged amino acid is selected from the group consisting of aspartic acid, glutamic acid and natural and synthetic derivatives thereof. , According to still further features in the described preferred embodiments the imino acid sequence is selected from the group consisting of SEQ ID NO: 4, 12-19 md 27-45. According to slill further features in the described preferred embodiments the eptide is selected from the group consisting of SEQ ID NOs. 4, 12-19 and 27-45. According to another aspect of the present invention there is provided a peptide oniprising at least 3 amino acid residues and less than 15 amino acid residues, the ^-^.,v>.. uiviuuiiig an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 12-19 and 27-44 wherein the peptide is capable of self-aggregating under physiological conditions. According to yet another aspect of the present invention there is provided a peptide selected from the group consisting ofSEQfDNOs: S, 10-11, 21-22 and 25. ' According to still another aspect of the present invention there is providcJ a peptide having an amino acid sequence selected from the group consisting of SEQ ID N0s:4, 12-19 and 27-44. According lo an addiiional aspect of the present invention there is provided a peptide having an amino acid sequence selected from the group consisting of SEQ ID N0s:8, 10-n and 21-22, According to >et an additional aspect of the present invention there is provided a method of treating or preventing an amyloid-associated disease in an individual, the method compnsing providing lo the individual a therapeutically effective amount of a peptide having at least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence as set forth in SEQ ID NO: 7. According to still an additional aspect of the present invention there is provided a method of treating or preventing an amyloid-associated disease in an individual, the method comprising providing to the individual therapeutically effective amount of a peptide having at least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence selected from the group consisting of SEQ ID KOs: 4,12-19 and 27-45. According to still further features in the described preferred embodiments the peptide is an active ingredient of a pharmaceutical composition which also includes a physioiogicany acceptable carrier. According to a further aspect of the present invention there is provided a method of treating or preventing an amyloid-associated disease in an individual, the method comprising providing to the individual a therapeutically effective amount of a peptide selected from the group consisting of SEQ ID NOs: 8, lO-l 1, 21-22 and 25, wherein the peptide is an active ingredient of a pharmaceutical compositions which also includes a physiologically acceptable carrier. According to yet a further aspect of the present invention there is provided a method of treating or preventing an amyloid-associated disease in an individual, the method comprising providing to the individual a therapeutically effective amount of a peptide selected from ihe group consisting of SEQ ED NOs: 4, 12-19 and 27-45. According to still a fijrther aspect of Ihe present invention there is provided a method of treating or preventing an amyloid-associated disease in an individual, the method comprising providing to the individual therapeutically effective amount of a peptide having at least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 10-11, 21-22 and 25, wherein the peptide is an active ingredient of a pharmaceutical composition which also includes a physiologically acceptable carrier. According to still further features in the described preferred embodiments the peptide is expressed &om a nucleic acid construct. According to siilJ a further aspect of Ihe present invention there is provided a phannaceulical composition for treating or preventing an amyloid-associated disease comprising as an active ingredient a peptide having at least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence as set forth in SEQ ID NO: 7 and a pharmaceutically acceptable carrier or diluent. According to still a hirther aspect of the present invention there is provided a phaimaceutical composition for treating or preventing an amyloid-associated disease comprising as an active ingredient a peptide selected from the group consisting of SEQ ID NOs: 8, 10-11, 21-22 and 25 and a phannaceulically acceptable carrier or diluent. According to still a fiirther aspect of the present invention there is provided a phaimaceutical composition for treating or preventing an amyloid-associated disease comprising as an active ingredient a peptide having at least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 10-11, 21-22 and 25 and a pharmaceutically acceptable carrier or diluent. According to stiii a further aspect of the present invention there is provided a phannaceutica! composition for treating or preventing an amyloid-associated disease comprising as an active ingredient a peptide having at least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 12-19 and 27-45 and a phannaceuticaUy acceptable carrier cr diluent. According to stiil a further aspect of the present invention there is provided a pharmaceutical composition for treating or preventing an amyloid-associated disease comprising as an active ingredient a peptide selected from the group consisting of SEQ ID NOs: 4, 12-19 and 27-45 and a pharmaceulicaily acceptable carrier or diluent. According to still a further aspect of the present invention there is provided a nucleic acid construct comprising a polvnucleotide segment encoding a peptide having at least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence as set forth in SEQ [D NO; 7, According lo stiil a further aspect of the present invention there is provided A nucleic acid construct comprising a polynucleotide segment encoding a peptide selected from the group consisting of SEQ ID NOs: S, 10-11,21-22 and 25. According to sliU a further aspect of the present invention there is provided a nucleic acid construct comprising a po!>'nucieotide segment encoding a peptide selected irom the group consisting of SEQ ID NOs: 4, 12-19 and 27-45. According to still a {\irther aspect of the present invention there is provided an antibody or an antibody fragment comprising an antigen recognition region capable of binding a peptide including at least 3 amino acid residues and less than 15 amino acid residues, the peptide including an amino acid sequence as set forth in SEQ ID NO; 7. According to still a fWther aspect of the present invention there is provided a pharmaceutical composition for treating or preventing an amyloid-associated disease comprising as an active ingredient an antibody or an antibody fragment having an antigen recognition region capable of binding a peptide including at least 3 amino acid residues and less than 15 amino acid residues, the peptide, including an amino acid sequence as set forth in SEQ ID NO: 7. According to still a further aspect of the present invention there is provided a method of treating or preventing an amyloid-associated disease in an individual, the method comprising providing to the individual therapeutically effective amount of an antibody or an antibody fragment having an antigen recognition region capable of binding a peptide including at least 3 amino acid residues and less than ! 5 amino a> residues, the peptide including an amino acid sequence as set forth in SEQ ID KO: ' According lo slill further fearures in the described preferred embodiments 1 peptide flirlher comprising at least luo serine residues at a C-terminus thereof According to stil! flirther fcarures in the described preferred embodiments I peptide is a linear or cyclic peptide. According lo slill further feamres in the described preferred embodiments t peptide further includes at least one beta-breaker amino acid. According lo still further feaaires in the described preferred embodiments t beta-beaker amino acid is proline. The present invention successftilly addresses the shortcomings of the present known configurations by providing novel peptides, composilions and methods, whic can be used to diagnose and treat amyloid associated diseases such as type D Diabett mellitus. BRIEF DESCRIPTION OF THE DRAWINGS The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes oi illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what Is believed to be the most useful and readily understood description of the prindples and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fimdamenlal understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. In the drawings: FIG. 1 is a schematic illustration depicting the self-assembly ability and hydrophobicity of a group of peptides &om a number of amyloid proteins as deduced using Kyle and Doiitile scale. Note, that no correlation is observed between hydrophobicity and the amyloidogenic potential of the analyzed peptides. The only apparent indication for potential am\loid fibril formation in this group of pqitide is a combination of aromatic nature and minimal length. FIGs. 2a-c are schematic illustrations of amyloid binding with the inhibitory aromatic reagents: Ro 47-lS\6/00! (Figure 2a). Thioflaviii T (Figure 2b) and CR dye (Figure 2c). FIGs. 33-c are schematic lilu.strations o[ a primary sequence companson between human and rodent LAPP 3r:d the synthetic peptides oflht present invention. Figure 3a is a sequence alignment of human and rodent lAPP. A block indicates a seven amino acid sub-sequence illustrating the major inconsistencies between the sequences. The "basic amyloidogenic unit" is presented by bold iencrs and underlined. Figure 3b illustrates the chemical structure of the wild type lAPP peptide (SEQ ID NO: 1). Figure Ic illustrates the primary sequences and SEQ ID NOs. of the peptides derived from the basic amyloidogenic unit. FIGs. 4a-b are graphs illustrating light absorbance at 405 nm as a ftinction of time during fibril formation thus reflecting the aggregation kinetics of lAPP-derived peptides. The following symbols are used: closed squares - NlA, opened circles -G3A, closed circles - wild t>-pe, opened triangles - L6A, opened squares - ISA and closed triangles - F2A. FIG. 5 is 3 histogram depicting mean particle size of assembled LAPP peptide and derivatives as measured by light scattering. Each column represents the results af 3-5 indqjeadent measurements. FIGs. 6a-n are photomicrographs illustrating Congo R«l binding to pre-issembled lAPP peptides. Normal field and polarized field micrographs are shdwn ■espectively for each of the following aged peptide suspensions: NIA peptide Figures 6a-b), F2A peptide (Figures 6c-d), G3A peptide (Figures 6e-0, wild type )eptide (Figures 6g-h), I5A peptide (Figures 6i-j) and L6A (Figures 6k-l). FIGs. 7a-f are electron micrographs of "aged" lAPP peptide and derivatives. ■JIA peptide (Figure 7a), F2A peptide (Figure 7b), G3A peptide (Figure 7c}, wild ype peptide (Figure 7d), I5A peptide (Figure 7e} and L6A (Figure 7f|- The indicated :aie bar represents 100 nm. 1 j-j. on li tt iiucicic acia sequence alignment of wild type hlAPP and a corresponding sequence modified according to a bacteria! codoti usage. Modified bases are underlined- FIG. 8b is a schematic illustntion of the pMALc2x-NN vector which is used for cytoplasmic expression of the 4S kDa MBP-LAPP protein. The V8 Ek cleavage site and the (His)6 lag are fused C-:erminaI!y to the malE tag vector sequence. A factor JTc cleavage site for removal of the MBP tag is indicated. FIG. 9 is a protein gel GelCode Blue staining depicting bacteria! expression and purification of MB? and MBP-L\PP flision protein. Bacterial cell extracts were generated and proteins were purified on an amylose resin column. Samples including 25 fig protein were loaded in each of Lanes 1-3 whereas 5 pg protein were loaded on each of lanes 4-5. Proteins were resolved on a 12 % SDS-PAGE and visualized with GeiCode Blue staining. A molecular weight marker is indicated on the left. Lane 1 -0,5 mM IPTG-induced soluble extract of MBP. Lane 2 - O.l mM IPTG-induced soluble extract of MBP-LAPP. Lane 3 - 0.5 mM IPTG-mduced soluble extract of MBP-IAPP. Lane 4 - purified MBP. Lane 5 - purified MBP-IAPP. An arrow marks the MBP-L\PP. FIGs. lOa-b are a dot-blol image (Figure 10a) and densitometric quantitation thereof (Figure 10b) depicting putative amyloidogenic sequences inhlAPP, FIG. 11 is a graphic illustration depicting light absorbance at 405 nm as a function of time during fibril formation thus refl,ecting the aggregation kinetics of L\PP-derived peptides (SEQ ID NOs. 14-19). The following symbols are used: closed squares - FLVHSS, opened circles - FLVHS, closed diamonds - NFLVHSS, opened hiangles - NFLVHSSNN, opened squares - FLVH and closed triangles -NFLVH. FIGs. 12a-f are photomicrographs illustrating Congo Red binding to pre-assembied lAPP peptides. Polarized field micrographs are shown for each of the following one day aged peptide suspensions: NFLVHSSNN peptide (Figures 12a), NFLVHSS (Figure !2b), FLVHSS (Figure I2c), NFLVH (Figure 12d), FLVHS (Figure I2e) and FLVH (Figure 12f). FIGs. 13a-f are electron micrographs of "aged" lAPP peptides. NFLVHSSNN peptide (Figures 13a), NFLVHSS (Figure 13b), FLVHSS (Figure 13c), NFLVH (Figure l3d), FLVHS (Figure 13e) and FLVH (Figure 131). The indicated scale bar represents lOOnni. FlGs. 14a-f are graphs showing secondary structures in Ihe insoluble L\PP aggregates as determined by Fourier transformed infrared spectroscopy. NFLVHSSNN peptide (Figures I4a\ NFLVHSS (Figure 14b}, FLVHSS (Figure 14c), NFLVH (Figure Ud), FLVHS i Figure 1-Jcl and FLVH (Figure ]40. FIG. 15 is a chemical slrLicturc of a previously reported amyloidogenic peptide fragment of Medin [Haggqvist (1999) Proc. Natl, Acad. Sci. USA 96:8669-S674]. FIGs. I6a-b are graphs iUustrating light absorbance at 405 nm as a function of time during fibril formation thus reflecting the aggregation kinetics of Medin-deri'/sd peptides. Figure i6a illustrates a short-term kinetic assay. Figure 16b illustrates a long-term kinetic assay. FIGs. 17a-f are electron micrographs of "aged" Medin-derived peptides, NFGSVQFA - Figures ]7a, NFGSVQ - Figure 17b, ^a^GSV - Figure 17c, FGSVQ -Figure I7d, GSVQ - Figure I7e and FGSV - Figure 17f TTie indicated scale bar represents 100 nm. FIGs. 18a-f are photomicrographs illustrating Congo Red bindmg to pre-assembled Medin-derived peptides. Polarized field micrographs are shown for each of the following aged peptide suspensions: NFGSVQFA - Figures 18a, NFGSVQ -Figure l8b, NFGSV - Figure I8c, FGSVQ - Figure 18d, GSVQ - Figure 18e and FGSV-Figure 18f. FIGs. I9a-c depict the effect of an alanine mutation on the amyloidogenic features of the hexapeptide amyloidogenic fragment of Medin. Figure 19a - is a graph illusfrating light absorbance at 405 nm as a function of time during fibril formation thus reflecting the aggregation kinetics of Medin-derived alanine mutant; Figure 19b is an electron micrograph of "aged" Medin- derived alanine mutant. The scale bar represents 100 nm; Figure 19c - is a photomicrograph illustrating Congo Red binding to pre-assembled Medin-derived pep tide-mutant. FIGs. 20a-b are the amino acid sequence of human Calcitonin (Figure 20a) and chemical structure of an amyloidogenic peptide fragment of human Calcitonin (Figure 20b), Underlined are residues 17 and 18 which are important to the oligomerizalion stale and hormonal activity of Calcitonin [Kazantzis (2001) Eui. J. BiQchem.269-.780-79!l. FIGs. 21a-d ar-: electron micrographs of "aged" Calcitonin-derived peptides. DFNKF - Figure 21a. DFINK - Figure 21b, FNKP - Figure 2 tc and DFN - Figure 21d. TTie indicated scale bar represents 1 CO nm. FIGs. 22a-d are photomicrcgraphs illustrating Congo Red binding to pre-assembled Calcitomn-deri\ed peptides. Polarized field micrographs are shown for each of the following aged peptide suspensions: DFNKF - Figure 22a, DFNK -Figure 22b, FNKF - Figure 22c and DFN - Figure 22d. FIG. 23 is a graphic iiiustraiion showing secondary structures in the insoluble Calcitonin aggregates as determined by Fourier transformed infrared spectroscopy. FlGs- 24a-c depict the effect an alanine mutation on the amyloidogenic features of the pentapeptidc amyloidogenic fragment of Calcitonin. Figure 24a is an electron micrograph of "aged" Calcitonin-derived alanine mutant. The scale bar represents 100 nm; Figure 24b - is a photomicrograph illustrating Congo Red binding to pre-assembled Calcilomn-derived peptide mutant; Figure 24c is a graph showing secondary structures in the mutant peptide as determined by Fourier transformed infrared spectroscopy. FIG. 25 is an electron micrograph depicting self-assembly of "aged" Lactotransferrin-derived peptide. The scale bar represents 100 nm. FIG. 26 is an electron micrograph depicting self-assembly of "aged" Senim amyloid A protein-derived peptide. The scale bar represents 100 nm. FIG. 27 is an election micrograph depicting self-assembly of "aged" BriL-derived peptide. The scale bar represents 100 nm. FIG. 28 is an electton micrograph depicting self-assembly of "aged" Gelsolin-derived peptide. The scale bar represents 100 nm. FIG. 29 is an electron micrograph depicting self-assembly of "aged" Serum amyloid P-derived peptide. The scale bar represents 100 nm. FIG. 30 is an electron micrograph depicting self-assembly of "aged" Immunoglobulin light chain-derived peptide. The scale bar represents 100 nm. FIG. 31 is an electron micrograph depicting self-assembly of "aged" Cystatin C-derived peptide. The scale bar represents 100 nm. riu. jz IS an electron micrograph depicting self-assembly of "aged" Transthyretin-derived peptide. The scale bar represents lOOnm. FIG. 33 is an electron micrograph depicting self-assembly of "aged" Lysozyme-derived peptide. Tne scale bar represents 100 nm. FIG. 34 is an electron micrograph depicting se)f-asscniblv of "aged" Fibrinogen-derived peptide. The scale bar represents 100 run. FIG. 35 is an electron micrograph depicting self-assembly of "aged" insulin-derived peptide. The scale bar represents 100 nm. FIG. 36 is an electron macrograph depicling self-assembly of "agsd" Prolactin-derived pepiice. TVie icalebar represents lOOnm. FIG. 37 is an electron micrograph depicting self-assembly of "aged" Be'.:i 2 microgtobu!in-derived peptide. The scale bar represents 100 nm. FIG. 38 is a graphic represemation of the effect of an inhibitory peptide on lAPP self-assembly. Squares - '-viid t>pe (wt) L-VPP peptide; triangles - wtTAPP -inhibitory peptide; circles - no peptides. FIG. 39 is a graphic illustration depicting light absorbance at 405 nm as a function of time dunng fibril formalicn thus reflecting the aggregation kinetics of lAPP-derived peptides (SEQ ID NOs. 46-49), FIG. 40 is a histogram representation illustrating turbidity of lAPP analogues following seven day aging. FIG. 41a-f are electron micrographs of "aged" lAPP analogues, NFGAILSS -Figure 4Ia; NFGAILSS - Figure 41b; N7GAILSS - Figure 41c; NLGAJLSS - Figure 41d; NVGAILSS - Figure 41e and NAGAJLSS - Figure 41f. The indicated scale bhr represents 100 nm. FIGs. 42a-c illustrate the binding of LAPP- NFGAILSS to analogues of the minimal amyioidogenic sequence SNNXGAILSS (X = any natural amino acid but cysteine). Figure 42a shows short exposure of the bound peptide-array. Figure 42b shows long exposure of the bound pepti de-array. Figure 42c shows qaantitation of the short exposure (Figure 42a) using densitometry and arbitrary units. DESCRIPTION OF THE PREFERRED EMBODjMENTS The present invention is of :iovei peptides antibodies directed thereagainst, compositions including same and methods of utilizing each for diagnosing or treating amyloid associated diseases such as t;.pe n Diabetes mellitus. The principles and operalion of the present invention may be belter understood with reference to the dravvings and accompanying descriptions. Before explaining at least on-^ embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of constmction and the arrangcmenl of the components set forth in the foilowing description or illuslraied in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting-Numerous therapeutic approaches for prevention of amyloid fibril formation or disaggreagtion of amyloid material have been described in the prior art. However, current therapeutic approaches are limited by cytotoxicity, non-specificity and delivery bamers. While reducing the present invention to practice and while searching for a novel therapeutic modality to amyloid associated diseases, such as 0 diabetes mellitus, the present inventor has identified a sequence characteristic of amyloid fomjing peptides which directs fibril formation. This finding suggests that ordered amyloidogenesis involves a specific pattern of molecular interactions rather than the previously described mechanism involving non-specific hydrophobic interactions [Petkova (2002) Proc. Natl. Acad. Sci. U S A 99:16742-16747]. As is further illustrated hereinbelow and in the Examples section which follows, the present inventor attributed a pivotal role for aromatic residues in amyloid formation. The involvement of aromatic residues in the process of amyloid formation is in-line with the well-established role of ju-such interactions in molecular recognition and self-assembly [Gillard et ai (1997) Chem. Eur. J. 3: 1933-40; Claessens and Stoddarl, (1997) J. Phys. Org. Chem. 10: 254-72; Shetty el al (1996) J. Am. Chem. Soc. 118; 1019-27; McGuaghey el al (1998) ^-stacking interactions: Alive and well m proteins. J. Biol. Chem. 273, 15458-15463; Sun and Bernstein (1996) J. Phys. Chem. 100: 1334S-66]. n-stacking interactions are non-bonded inleractions which are formed ber-'.een planar aromatic rings. TTie steric constrains associated with the formation of those ordered stacking structures have a fundamental role in self-asseinbly processes that lead to the formation of supramolecular structures. Such rt-stncking interactions, which are probably entropy driven, play a central role in many biological processes such as stabilizaiion of the double-helix structure of DNA, core-packing ar^d stabilization of the tertiary structure of proteins, host-guest interactions, and porphvrin aggregation in solution [for funher review on the possible role ofit-stacking interaction in the self-assembly of amyloid fibrils see Gazit (2002) FASEB J. 16:77-83]. Identification of an aromatic sequence wliich is sufficient for mediating amyloid sel!'-assembly enables for the firs: time, to generate highly efficient diagnostic, prophylactic and iherapeutic peptides which can be utilized to treat or diagnose diseases characterized by amyloid plaque formation. Thus, according to one aspect of the present invention there is provided a peptide which includes the amino acid sequence sel forth in SEQ ID NO: 7 and is capable of self aggregation into fibnls. As is further described hereinbelow, peptides possessing self aggregation capabilities and modificants thereof can be utilized in diagnostic and therapeutic applications. The sequence set forth in SEQ ED NO: 7 includes at least one aromatic amino acid residue which, as is shown by the results presented in the Examples section, is pivotal to the formation of amyloid fibrils. It will be appreciated that aromaticity rather than hydrophobicity of the aromatic amino acid is the prevailing chemical feature in amyloid self-assembly as illustrated in Examples 36-39 of the Examples section. The aromatic amino acid can be any naturally occurring or synthetic aromatic residue including, but not limited to, phenylalanine, tyrosine, tryptophan, phenyl glycine, or modificants, precursors or functional aromatic portions thereof Examples of aromalic residues which can be used by the present invention are provided in Table 2 below. As is demonstialed by the results provided in the Examples section which follows, the present invention facilitates the design of peptides exhibiting varying degrees of self-aggregation kinetics and aggregate structure. As used herein, the phrase '■self-aggregation" refers to the capability of a peptide to form aggregates (e.g. flbnls) in an aqueous solution. The ability of a peptide to self-aggregate and the kinetics and type of such self-aggregation determines a use for the peptide in treating or diagnosing amyloid diseases. Since aggregation kinetics and aggregate structures are largely determined by the specific residue composition and possibly the length ofthe peptides generated (see Figure 1), the present invention encompasses both longer peptides (e.g., 10-50 amino acids) which include the sequences set forth in SEQ ID NOs: 4, 8, 10- i 9, 21 -22, 25 or 27-45, or shorter peptides (2-10 amino acid residues) including any of these sequences. Due to their self-aggregating nature these peptides can be used as potent diagnostic reagents- hi order to enhance the rate of amyloid formaiion, the peptides of the present invention preferably further include at least one polar and uncharged amino acid including but. not, limited to serine, threonine, asparagine, glutamine or natural or synthetic derivatives thereof (see Table 2). Additionally, the peptides ofthe present invention may fiirther include at least one pair of positively charged (e.g., lysine and arginine) and negatively charged (e.g., aspartic acid and glutamic acid) amino acids (e.g.i,SEQ ID NOs. 27-29). Such amino acid composition may be preferable, since as shown in Examples 21 ofthe Examples section, it is likely that electrostatic interactions between opposing charges may direct the formation of ordered antiparallel structure. Since the present inventors have identified the sequence characteristics governing fibril formation, the teachings of the present invention aiso enable design of peptides which would not aggregate into fibriis and be capable of either preventing or reducing fibril formation or disrupting preformed fibrils and thus can be used as a therapeutic agents. For example, a peptide encompassed by SEQ ID NO: 9, 10, 11, 17, 19, 25 or 30 can be utilized for therapy since as is shown in the Examples section which follows, such a peptide displays no aggregation (SEQ ID NO; 9) or slow aggregation kinelics as compared to the wild type peptide (SEQ ID NOs; 9 and 10). Ii is conceivable that since amyloid formation is a very slow process, these peptide sequences will completely inhibit or significantly delay ;imyIoidosis under physiological condiiions- The term "peptide" as used herein encompasses native peptides (euher degradation products, synthetically s'rTil-hesized peptides or recombinant peptides} and peplidoniimetics (typically, synthclxally synthesized peplides), as well as pepioids and semipeploids ^^hich are pepiidc analogs, which may have, for example, modifications rendenng the peptides more stable while in a body or more capable of penetrating into cells. Such modifications include, but are not limited lo N" termmus modification. C terminus modification, peptide bond modification, including, but not limited to, CH2-NH, ai2-S. CH2-S=0, OC-NH, CH2-0, CH2'CH2, S=C-NH, CH=CH or CF-CH, backbone modifications, and residue modification. .\!ethods for preparing peplidomimetic compounds are well known in the an and are specified, for example, in Quanfilafivc Drug Design. C.A. Ramsden Gd., Chapter 17,2, F. Choplin Pergamon Press (1992). which is incorporated by reference as if fully set forth herein. Further details in this respect are provided hcreinunder Peptide bonds (-CO-NH-) within the peptide may be substituted, for example, by N-methy!ated bonds (-N(CH3)-C0-), ester bonds (-C(R)H-C-0-0-C(R}-N-), ketomethylen bonds (-C0-CH2-), a-aza bonds (-NH-N(R)-CO-), wherem R is any alkyi, e.g., methyl, caiba bonds (-CH2-NH-), hydrt)xyethylene bonds (-CH(0H)-CH2-), Ihioamide bonds (-CS-NH-), olefinic double bonds (-CH=CH-), retro amide bonds (-NH-CO-), peptide derivatives (-N(R)-CH2-C0-), wherein R is the "normal""side chain, naturally presented on the carbon atom. These modifications can occur at any of the bonds along the peptide chain and even at several (2-3) at the same time. Natural aromatic amino acids, Trp, Tyr and Phe, may be substituted for synthetic non-natural acid such as Phenylglycine, TIC, naphthylelanine (Nol), ring-methylated derivatives of Phe, halogenated derivatives of Phe or o-methy!-Tyr. in addition to the above, the peptides of ihe present invention may also include one or more modified amino acids or one or more non-amino acid monomers (e.g. fatty acids, complex carbohydrates etc). As used herein in the specification and in the claims section below the term "amino acid" or "amino acids" is understood to include the 20 naturally occurring amino acids; those amino aclJs often modified post-translationa!ly in vivo, including, for example, hydroxvproline, phosphoserine and phosphothreonine; and other unusual amino acids including, but not limited to. 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucme and omithine. Furthermore, the term "amino acid" includes both D- and L-amino acids. Tables I and 2 below list naturally occurring amino acids (Table 1) and non- convenlional or modified amino acids (Table 2| which can be used with the present invention. Since the present peptides are preferably utilized in therapeutics or diagnostics which require the peptides lo be in soluble form, the peptides of the present invention preferably include one or more non-natural or natural polar amino acids, including but not limited to serine and threonine which are capable of increasing peptide solubility due to their hydroxyl-containing side chain. For therapeutic application, the peptides of the present invention preferably further include at least one beta-sheet breaker amino acid residue such as proline (e.g., SEQ ID NO. 45, see background section) which is characterized by a limited phi angle of about -60 to +25 rather than the n.pical beta sheet phi angle of about -120 to -140 degrees, thereby disrupting the beta sheet sirucnire of the amyloid fibril. The peptides of the present invention are preferably utilized in a linear form, although it will be apprecialed that in cases where cychzation does not severely interfere with peptide characteristics, cyclic forms of the peptide can also be utilized. Cyclic peptides can either be synthesized in a cychc form or configured so as to assume a cyclic form under desired conditions (e.g., physiological conditions). Thus, the present invention provides conclusive data as to Ihe identity of the structural determinant of amyloid peptides, which directs fibril assembly. As such, the present invention enables design of a range of peptide sequences, which can be utilized for prevention/treatment or diagnosis of amyloidosis. It will be appreciated that the present inventor could identify the consensus aromatic sequence of the present invention (SEQ\ID NO: 7) in numerous amyloid related proteins (see Examples 6-35 of the Examples section). Thtis, the present invention enables accurate identification of amyloidogenic fragments in essentially all amyloidogenic proteins. Furthermore, the fact that small aromatic molecules, such as Ro 47-1816/001 [Kuner et al. (2000) J. Biol. Chem. 275:1673-8, see Figure laj and 3-p-toluoyi-2-[4'-(3-diethylaminopropoxy)-phnyl]-benzofuran [Twyman (1999) Teh-ahedron Letters 40:9383-9384] have been demonstrated effective in inhibiting the polymerization of the beta polypeptide of Alzheimer's disease [Fir.deis et al. (2000) Biochem. Biophys-Acta 1503:76-841, while amyloid specific dyes such as Congo-Red (Figure 2b) and thioflavin T (Figure 2c), which contain aromatic elements are generic amyloid formation inhibitors, substantiate the recognition motif of the present invention as sufficient for amyloid self-assembly. The availability of the peptides of the present invention allows for the generation of antibodies directed thereagainst, which may be used lo dissociate or prevent the formation of amyloid plaques (U.S. Pat. No. 5,688,561). The term "antibody" refers to intact antibody molecules as well as functional fragments thereof, such as Fab, F(ab'}:, and Fv that are capable of binding to macrophages. These functional antibody fragments are defined as follows: (i) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molec"ule, can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a ponion of one heavy chain; (ii) Fab', the fragment of an antibody molecule that can be obtained by treating whole antibody with pepsin, followed by reduction, lo yield an intact light chain and a portion of the heavy chain; Uvo Fab' fragments are obtained per antibody molecule; (iii) {Fab');, the fragment of the antibody that can be obtained by treating whole antibody with the en2yme pepsin without subsequent reduction; F(ab'): is a dimer of two Fab' fragments held together by hvo disulfide bonds; (iv) Fv, defined as a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as t\vo chains; and (v) Single chain antibody ("SCA"), a genetically engineered molecule containing the variable region of the light chain and the variable region of the heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule. Methods of making these fragments are known in the art. (See for exaftiple, Ffarlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Hew York, 1988, incorporated herein by reference). Methods of generating antibodies (i.e., monoclonal and polyclona!) are well knovm in the art. Antibodies may be generated via any one of several methods known in the art, which methods can employ induction of in vivo production of antibody molecules, screening immunoglobulin libraries or panels of highly specific binding reagents as disclosed [Orlandi D.R. et al. (!9S9) Proc. Natl. Acad. Sci. 86:3833-3837, Winter G. et al. (1991) Nature 349:293-299] or generation of monoclonal antibody molecules by continuous cell lines in culture. These include but are not limited to, the hybridoma technique, the human B-ce![ hybridoma technique, and the Epstein-Bar-Vinis (EBV)-hybridoma technique [Kohler G-, et al, (1975) Nature 256:495-497, Kozbor D-, et al, (1985) J, Immunol, Methods Si :31-42, Cole R.J. et al. (!9S3)Proc. Natl. Acad. Sci. 80:2026-2030, Cole S.P. et al 09S4) Mol. Cell. Biol. 62:109-120], Antibody fragments according to the present invention can be prepared by proteolytic hydrolysis of the antibody or by expression in E. coli or mammalian c^Us (e.g. Chinese hamster ovary cell culture or other protein expression systems) of DNA encoding the fragment. Antibody fragmenls can be obtained bv pepsin or papain digestion of whole antibodies by conventional methods. For example, antibody fragmenls can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment denoted F(ab')2. This fragment can be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryi groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab' monovaienl fragments. Alternatively, an enzymatic cleavage using pepsin produces two monovalent Fab' fragments and an Fc fragment directly. These methods are described, for example, by Goldenberg, U.S. Pal. Nos. 4,036,945 and 4,331,647, and references contained therein, which patents are hereby incorporated by reference in their entirely. See also Porter, R. R,, Biochem. J., 73; 119-126, 1959. Other methods of cleaving antibodies, such as separation of heavy chains to form monovalent light-heavy chain fragmenls, further cleavage of fragments, or other enzymatic, chemical, or generic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody. Fv fragments comprise an association of VH and VL chains. This association may be noncovalent, as described in Inbar et al., Proc. Nat'l Acad. Sci. USA 69:2659-62, 1972. Alternatively, the variable chains can be linked by an intermolecular disulfide bond or cross-linked by chemicals such as glutaraldehyde. Preferably, the Fv fragments comprise VH and VL chains cormected by a peptide linker. These single-chain antigen binding proteins (sFv) are prepared by constructing a structural gene comprising DNA sequences encoding the V'H and VL domains cormected by an oligonucleotide. The stmctural gene is inserted into an expression vector, which is subsequently introduced into a host cell such as E. coli. The recombinant host cells synthesize a single polypeptide chain with a linker peptide bridging the two V domains. Methods for producing sFvs are described, for example, by Whitlow and Filpuia, Methods, 2: 97-105, 1991; Bird et al., Science 242:423-426, I98S; Pack et a!., Bio/Technology 11:1271-77, 1993; and Ladner el a!., U.S. Pat. No. 4,946,778, which is hereby incorporated by reference in its entirely. Another form of an anti"body fragment is a peptide coding for a single complementariW-detemiining region (CDR). CDR peptides ("mmimai lecognition units") can be obtained by constracUne genes encoding the CDR of an antibody of interest. Such genes are prepared, for example, by using the polymerase chain reaction lo synthesize the vanab!e region from RN'.A of antibody-producing cells. See, for example, Larrick and Fry, Meihods, 2: 106-10, 1991. For human applications, the antibodies of the present invention are preferably humanized. Humanized forms of non-human (e.g., murine) antibodies are chimenc molecules of immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab').sub.2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues form a complemenlar>' determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will include at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunogiobuh'n [Jones et al., NaUire, 321:522-525 (1986); Rjechmann et al.. Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)]. Methods for humanizing non-human antibodies are wet! known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, wlijch are l\picai!y taken from an import variable domain. Humanization can be essentially performed following ihe method of Winter and co-workers [Jones et al.. Nature, 32U522-525 (19S6); Riechmann et al., Kamre 332:323-327 (1988); Verhoeyen el al.. Science, 239:1534-1536 (198S)], by substituting rodent CDRs or CDR Si^quences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric anlibodies (U.S. Pat. No, 4,816,567), wherein substantially less than an intact human vanable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are rvpically human antibodies in which some CDR residues and possibly some FR residues are substitnted by residues from analogous sites in rodent antibodies. Human antibodies can also be produced using various techniques icnown in the art, including phage display libraries [Hoogenboom and Winter, J. Mo!. Bioi., 227:381 (1991); Marks el a!., J. Mol. Biol, 222-.581 (1991)1. The techniques of Cole et al. and Boemer et ai. are also available for the preparation of human monoclonal antibodies (Cole et al.. Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boemer et al., ]. Immunol., 147(l):86-95 (1991)]. Similarly, human can be made by introducing of human immunogiobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been parlially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks el al., Bio/Technology 10, 779-783 (1992); Lonberg et a!., Nature 368 856-859 (1994); Morrison, Namre 368 812-13 (1994); Fishwild et al., NaUire Biotechnology 14, 845-51 (1996); Neuberger, Nature Biotechnology !4, 826 (1996); Lonberg and Huszar, Intern. Rev. Immunol. 13 65-93 (1995). As is mentioned hereinabove, one specific use for the peptides of the present invention is prevention or treatment of diseases associated with amyloid plaque formation. Thus, according to yet acinhcr aspect of the present in\'ention. there is provided a method of treating .m amyloid-associated disease in an individual. Preferred individual subjects aecor^nng to tb.e present in\'cntion are i":";amma!s such as canines, felines, ovines. porcines, c.;uines, bo\'ines, humans and the like. The term "treating" refers to reducing or pre\'enting am>1oid plaque fonnalion. or substantially decreasing plaque occurrence in the atTeeted tissue. The phrase "amvloid plaque" refers to fibrillar am>'loid as well as aggregated but not fibrillar amyloid, hereinafter "prolofibrillar amyloid", which may be pathogenic as wcli. For example, an aggregated but not necessarily fibrillar form of lAPP was found to be toxic in culture. As shown by Anagui-ar.o and co-wotkcrs ((2002i Biochemistp.-41:11338-43] protofibrillar LAPP, like protof'ibrillar o-sviiucclin, uhich is iniplicated in Parkinson's disease pathogenesis, permeabilizxd synthetic vesicles by a pore-like mechanism. The formation of the of the lAPP amyloid pore was temporally correlated to the tbrmation of early LAPP oligomers and disappearance thereof to the appearance of amyloid fibnls. These results suggest that protofibrillar LAPP may be critical to t>pe li diabetes mellitus as other protofibrillar proteins are critical to the development of Alzheimer's and Parkinson's diseases. Amyloid-associated diseases treated according to the present invention include, but are not limited to, type II diabetes mellitus, Alzheimer's disease (AD), early onset AJzheimer's disease, late onset Alzheimer's disease, presymptomatic Alzheimer's disease, Perkinson's disease, SAA amyloidosis, hereditary Icelandic syndrome, multiple myeloma, medullary carcinoma, aortic medical amyloid. Insulin injection amyloidosis, prion-systematic amyloidosis, chronic inflammation amyloidosis, Huntington's disease, senile systemic amyloidosis, pituitary gland amyloidosis, Hereditary renal amyloidosis, familial British dementia, Finnish hereditary amyloidosis, familial non-neuropathic amyloidosis [Gazit (2002) Curr, Med, Chem, 9-,1667-!675] and prion diseases including scrapie of sheep and goats and bovine spongiform encephalopathy (BSE r of catde [Wilesmith and Wells (1991) Curr Top Microbiol immuno! 172: 21-38] a,nd human pnon diseases including (i) Icuru, (ii) Creutzfeldt-Jakob Disease (CJD). (iii) Gerstmann-Streussler-S he inker Disease (GSS), and (iv) fatal familial insomnia (FFI) [Gajdusek (1977) Science 197: 943-960; Medori, TritschJer et al. (1992) N Engl J Med 326: 444-449]. The method includes providing to the individual a therapeutically effective amount of the peptide of the present invention. The peptide can be provided using any one of a variety of delivery methods. Delivery methods and suitable formulations are described hereinbelow with respect to pharmaceutical compositions. It will be appreciated that when utilized for treatment of amyloid diseases, the peptide of the present invention includes an amino acid sequence suitable for preventing fibril formation, reducing fibri! formation, or disaggregating formed aggregates by competitive deslabilization of the preformed aggregate. For example, SEQ ID NO: 45 can be utilized for treatment of amyloid diseases, particularly type U diabetes mellitus since as shown in Example 35 of the Examples section which follows, such a sequence interferes with LAPP self-assembly as demonstrated by the decreased ability of the amyloidogenic peptide to bind ihioflavin T in the presence of an inhibitory peptide. Alternatively, the peptides set forth in SEQ ID NOs: 10 or 11 can be used as potent inhibitors of type II diabetes since a^ shown in the Examples section which follows, substitution of either leucine or isoleucine in the peptide elicits very slow kinetics of aggregation. Since amyloid formation in vivo is a very slow process, it is conceivable that under physiological conditions'no fibrilization will occur upon the substitution of isoleucine or leucine to alanine in the context of the full length lAPP. Alternatively, self-aggregating peptides such as those set forth in SEQ ID NOs. 17, 19 and 28-30, can be used as potent inhibitors of amyloid fibrilization, since such peptides can form heteromolecular complexes which are not as ordered as the homomolecular assemblies formed by amyloid fragments. It will be appreciated that since one of the main obstacles in using short peptide fragments in therapy is their proteoKtic degradation by stereospecific cellular proteases, the peptides of the present invention are preferably synthesized from D-isomers of natural amino acids [i.e., inverse peptide analogues, Tjemberg (1997) j. Biol. Chem. 272:12601-5. Gazit (2002) Curr. Med. Chem. 9:1667-1675], Aaainonally, the peptides of the present invention include retro, inverso and retro-inverso analogues thereof. It will be appreciated that complete or extended partial retro-inverso analogues of hormones have generally been found io retain or enhance biological activity. Retro-in^■ersion has also found application in the area of rational design of enzyme inhibitors (see U.S. Pat. No. 6,261,569). As used herein a "retro peptide" refers to peptides which are made up of L-amino acid residues which are assembled in opposite direction io the native peptide sequence. Retro-inverso modification of naturally occurring polypeptides involves the synthetic assembly of amino acids with a-carbon stereochemistry opposite lo that of the corresponding L-amino acids, i.e., D- or D-allo-amino acids in inverse order lo the native peptide sequence. A rerlo !n\'erso analogue, thus, has reversed termini and reversed direction of peptide bonds, \'^hi!e essentially maintaining the topology of the side chains as in the native peptide sequence. Additionally, since one of the main issues in amyloid fibril formation is the transition of the amyloid polypeptide from the native form to stacked p-slrand structure, inhibitory peptides preferably include N-methylated amino acids which constrain peptide-backbone due to steric efi'ects [Kapumiotu (2002) 315:339-350], For example, aminoisobutyric acid (Aib or methyl alanine) is known to stabilize an a-helical strucuire in short natural peptides. Furtberraore, the N-raethylation also affects the inlermolecular NH to CO H-bond\ng ability^ thus suppressing the formation of multiplayer p-stiands, which are stabilized by H-bonding interactions. It will be further appreciated that addition of organic groups such as a cholyl groups to the N-tenninal or C-tenninal of the peptides of the present invention is prefened since it was shown to improve potency and bioavailability (e.g., crossing the blood brain barrier in the case of neurodegenerative diseases) of therapeutic peptides [Findeis (1999) Biochemistry 38:6791-68001. Furthermore, introducing a charged amino acid to the recognition motif, may result in electrostatic repulsion which inhibits further growth of the amyloid fibrils [Lowe (2001) 3. Mol. Biol. 40-.7SS2-7889]. As mentioned hereinabove, the antibodies of the present invention may also be used to treat amyloid-associaled diseases. .iii, ptpimci ajiu/ur aniiDodies of the present invention can be provided to an individual j7er se, or as part of a pharmaceutical composition where it is mixed with a pharmaceulically acceptable carrier. As used herein a "phannaceunca! composition" refers to a preparation of one or more of the active ingredients described herein with other chemica] components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to f:!ciliiale administration of a compound to an organism. Herein the term "active ingredient" refers to the peptide or antibody preparation, which is accountable for the biological effect. Hereinafter, the phrases "physiologically acceptable carrier" and "phannaceutically acceptable canrier" which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and propenies of the administered compound. /\n adjuvant is included under these phrases. One of the ingredients included in itie phannaceutically acceptable carrier can be for example polyethylene glycol (PEG), a biocompatible polymer with a wide range of solubility in both orgamc and aqueous media (Mutter et a). (1979). Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium caibonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Hasten, PA, latest edition, which is incorporated herein by reference. Suitable routes of admim'stration may, for example, include oral, rectal, transmucosal, especially transnasal, intestinal or parenleral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intiathecai, direct intraventricular, intravenous, inrlaperitoneal, intranasal, or intraocular injections. Alternately, one may administer a preparation in a local rather than systemic manner, for example, via injection of the preparalion directly into a specific region of apatienVsbody. Pharmaceutical compositions of the present invention may be manufacmred by processes welt known in the art, e.g.. by means of conventional mixing, dissolving, granulating, dragee-making, levigal;ng, emulsifying, encapsulating, entrapping or lyophilizing processes, Pharmaceulicai compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically-Proper formulation is dependent upon the route of administration chosen. For injection, the active ingredients of the invention may be formulated in aqueous solutions, preferably in phy-sioiogically compatible buffers such as Hank's solution, Ringer's solution, or physiologicai saU buffer. For transmucosa! administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated readily by combining the active compounds with phamiaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsuliis, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcelluJose; and or physiologically acceptable polymers such as poiyvinylpyrroUdone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrroiidone, carbopol gel, polyethyiene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mi.xmres, Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of acuve compound doses. Pharmaceutical compositions, which can be used orally, include push-fit capsules made of gelatin as well as sotl. sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, bmders such as starches, lubricants such as talc or magnesium stcarate and, optionally, stabilizers, ti soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All tormulations for oral administration should be in dosages suitable for the chosen route of administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated m conventional manner. For administration by nasal inhalation, the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable jropellant, e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichloro-etiafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage init may be detennined by providing a valve to deliver a metered amount. Capsules iDd cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a lowder mix of the compound and a suitable powder base such as lactose or starch. The preparations described herein may be formulated for parenteral dministration, e.g., by bolus injection or continuous infiision. Formulations for ijeclion may be presented in unit dosage form, e.g., in ampoules or in muliidose^ Dntainers with optionally, an added preservative. The compositions may be ispensions, solutions or emulsions in oily or aqueous vehicles, and may coatain )rmulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic falty acids esters such as eihyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also comain suitable stabilizers or agents which increase the solubility of the aclivc irigredients to allow for the preparation of highly concentrated solutions. AJlematively, the active ingredient may be in powder form for constitution with a suilable vehicle, e.g., sterile, pyrogen-free water based solution, before use. The preparation of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa buller or othsr giycerides. Pharmaceutical compositions suilable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More speciScaUy, a therapeutically effective amount means an aniount of active ingredients effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determinaiion of a therapeutically effective amount is well within the capability of those skilled in the art. For any preparation used in the methods of the invention, the therapeutitally effective amount or dose can be estimated initially from in vitro assays. For example, a dose can be fonnulated in animal models and such information can be used to more accurately determine useful doses in humans. Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vilro, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utih'zed. The exact formulation, route of administration and dosage can be chosen by the individual physician in \iew of the patient's condition. [See e.g., Fingl,etal., (1975) "The Pharmacological Basis of Therapeutics", Ch 1 p. I]. Depending on the severity and responsiveness of the condition lo be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered will, of course, be dependent on the subject being treated, the sevcnry of the affliction, the manner of administration, the judgment of the prescribing physician, etc. Compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, v^-hich may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a govemraentai agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription dmgs or of an approved product insert. It will be appreciated that the peptides or antibodies of the present invention can also be expressed from a nucleic acid construct administered lo the individual employing any suitable mode of administration, described hereinabove (i.e., in-vivo gene therapy). Alternatively, the nucleic acid construct is introduced into a suitable cell via an appropriate gene delivery vehicle/method (transfeetion, transduction, homologous recombination, etc.) and an expre-ssion system as needed and then the modified cells are expanded in culture and returned to the individual (i.e., ex-vivo gene therapy). To enable cellular expression of the peptides or antibodies of the present invention, the nucleic acid construct of the present invention further includes at least one CIS acling regulatory element. As used herein, the phrase "cis aclmg regulatory element" refers to a polynucleotide sequence, preferably a promoter, which binds a trans acting regulator and regulates the transcription of a coding sequence Socated downstream thereto. Any available promoter can be used by the present methodology-, [n a preferred embodimenl of the present invention, the promoter utilized by the nucleic acid construct of the present invention is active in the specific cell population transformed. Examples of cell type-specific and/or tissue-specific promoters include promoters such as albumin that Is liver specific [Pinkert et a!., (1987) Genes Dev. 1:268-277], lymphoid specific promoters [Calam.e et al, (19S8) Adv. Immunol. 43:235-275]; in particular promoters of T-celi receptors [Winoto et al., (1989) EMBO J. 8:729-733] and immunoglobulins; [Baneri'i et a!. (1983) Cell 33729-740]. neuron-specific promoters such as the neurofiiament promoter [Byrne et al. (1989) Proc. Natl. Acad. Sci- USA 86:5473-5477], pancreas-specific promoters [Edlunch et al, (1985) Science 230:912-916] or mammary gland-specific promoters such as the milk whey promoter (U-S. Pat. No. 4,873,316 and European Application Publication No. 264,166). The nucleic acid construct of the present invention can fiirther include an enhancer, which can be adjacent or distant to the promoter sequence and can function in up regulating the transcription therefrom. The constructs of the present methodology preferably fiirther include an appropriate selectable marker and/or an origin of replication. Preferably, the construct utilized is a shuttle vector, which can propagate both in E. coH (wherein the construct comprises an appropriate selectable marker and origin of replication) and be compatible for propagation in cells, or integration in a gene and a tissue of choice. The construct according to the present invention can be, for example, a plasraid, a bacmid, a phagemid, a cosmid, a phage, a virus or an artificial chromosome. Currently preferred in vivo nucleic acid transfer techniques include transfection with viral or non-viral consnucts, such as adenovirus, lentivirus. Herpes simplex I virus, or adeno-associated virus (AAV) and lipid-based systems. Useful lipids for lipid-mediated transfer of the gene are, for example, DOTMA, DOPE, and DC-Chol [Todcinson et al.. Cancer Investigation. 14(1): 54-65 (1996)]. The most preferred constructs for use in gene therapy are viruses, most preferably adenoviruses, AAV, lenliviruses, or retroviruses. A viral construct such as a retroviral construct includes at least one transcripUona! promoter/enhancer or locus-defining element(s), or other elements that control gene expression by other means such as alternate splicing, nuclear RNA export, or posi-transiational modification of messenger. Such vector constructs also include a packai^ing signal, long terminal repeats (LTRs) or portions thereof, and positive and negative strand primer binding sites appropriate to the virus used, unless ii is already present in the viral construct. In addition, such a construct topically includes a signal sequence for secretion of the peptide or antibody &om a host ceil in which h is placed. Preferably the signal sequence for this purpose is a mammalian signal sequence. Optionally, the construct may aiso include a signal that directs polyadenylation, as well as one or more restriction sites and a translation termination sequence. By way o( example, such constructs will typically include a 5' LTR, a tRNA binding site, a packadng signal, an origin of second-slrand DNA synthesis, and a 3' LTR or a portion thereof Other vectors can be used that are non-viral, such as cationic lipids, polylysme, and dendrimers. Because of the self-aggregating nature of the peptides of the present invention it is conceivable that such peptides can also be used as potent detectors of amyloid fibrils/plaques in biological samples. This is of a special significance to amyloid-associated diseases sych as Alzheimer's disease wherein unequivocal diagnosis can only be made after postmortem e.xamination of:, brain tissues for the hallmark neurofibrillary tangles (NFT) and neuritic plaques. Thus, according to yet another aspect of the present invention there is provided a method of delecting a presence or an absence of an amyloid fibril in a biological sample. The method is effected by incubating the biological sample with a peptide of the present invention capable of co-aggregating with the amyloid fibril and detecting the peptide, to thereby detect the presence or the absence of amyloid fibril in the biological sample. A variety of peptide reagents, which are capable of recognizing conformational ensembles are known in the art some of which are reviewed in BuTsavich (2002) J. Med. Chem. 45(3); 541-58 and in Baltzer Chem Rev. !01(10):3153-63, The biological sample utilized for detection can be any body sample such as blood (semm or plasma), sputum, ascites fluids, pleural effusions, urine, biopsy specimens, isolated ceils and/or cell membrane preparation. Methods of obtaining tissue biopsies and body fluids from mammals are well known in the art. The peptide of the present invention is contacted with the biological sample under conditions suitable for aggregate formation (i.e., buffer, temperature, incubation lime elc); suitable conditions are described in Example 2 of the Examples section. Measures are taken not to allow pre-aggregaiion of peptides prior to incubation with the biological sample. To this end freshK' prepared peptide stocks are preferably used. Protein complexes within a biological sample can be detected via any one of several methods known in the art, which methods can employ biochemical and/or optical detection schemes. To faciiilate complex detection, the peptides of the present invention are highlighted preferably by a tag or an antibody. It will be appreciated that highlighting can be effected prior to, concomitant with or following aggregate formation, depending on the highlighting method. As used herein the term "tag" refers to a molecule, which exhibits a quantifiable activity or characteristic. A tag can be a fluorescent molecule including chemical fluorescers such as fluorescein or polypeptide fluorescers such as the green fluorescent protein (GFP) or related proteins (www.clontech.com). In such case, the tag can be quantified via its fluorescence, which is generated upon the application of a suitable excitatory light. Alternatively, a tag can be an epitope tag, a fairly unique polypeptide sequence to which a sjlecific antibody can bind without substantially cross reacting with other cellular epitopes. Such epitope tags include a Myc tag, a Flag tag, a His tag, a leucine tag, an IgG tag, a streptavidin tag and the like. Aitemalively, aggregate detection can be effected by the antibodies of the present invention. Thus, this aspect of the present invention provides a method of assaying or screening biological samples, such as body tissue or fluid suspected of including an amyloid fibril. It will be appTeciated that such a detection method can also be utilized in an assay for uncovering potential drugs useful in prevention or disaggregation of amyloid deposits. For example, the present invention may be used for high throughput screening of test compounds. Typically, the co-aggregating peptides of the present invention are radiolabeled, to reduce assay volume. A competition assay is then effected by monitoring displacement of the label by a lest conipound [Han (1996} J. Am. Chem-Soc, 1 lS:4506-7 and Esler (1996) Cheni- 271:8545-8]. It will be appreciated that the peptides of the present invention may also be used as potent detectors of amylotd deposits in-vivo. A designed peptide capable of binding amyloid deposits, labeled non-radioactively or with a radio-isotope, as is --veil known in the art can be administered to an individual to diagnose the onset or presence of amyloid-related disease, discussed hereinabove. The binding of such a labeled peptide after administration to amyloid or amyloid-like deposits can be detected by in vivo imaging techniques known m the art. The peptides of the present invention can be included in a dlagnoslic or therapeutic kit. For e.xample, peptide sets of specific disease related proteins or antibodies directed thereagainst can be packaged in a one or more containers with appropriate buffers and preservatives and used for diagnosis or for directing therapeutic treatment. TTius, the peptides can be each mixed in a single container or placed in individual containers. Preferably, the containers include a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers may be fonned from a variety of materials such as glass or plastic. In addition, other additives such as stabilizers, buffers, blockers and the like may also be added. The peptides of such kits can also be attached to a solid support, such as beads, array substrate (e.g., chips) and the like and used for diagnostic purposes. Peptides included in kits or immobilized to substrates may be conjugated to a detectable label such as described hereinabove. The kit can also include instructions for determining if the tested subject is suffering from, or is at risk of developing, a condition, disorder, or disease associated with amyloid polypeptide of interest. Additional objccis, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodimenis and aspects of the present invention as deiinealed hereinabove and as claimed in the claims section be'.ow finds experimental suppon in the following examples, EXA.\IPLES Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting tashion. Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include moleoular, biochemical, microbiological and recombinant DNA techniques. Such tecb^'iiques are thoroughly explained in the literature. See, for example, "Molecular Cloning: A laboratory Manual" Sambrook et al-, {19S9); "Current Prolocols in Molecular Biology" Volumes I-III Ausubei, R- M., cd. (1994); Ausubc! et al., "Current Protocols in Molecular Biology", John Wifey and Sons, Baltimore, Mar>'!and (1989); Perbai. "A Practical Guide to Molecular Cloning", John Wiley & Sons, New York (1988); Watson et al., "Recombinant DNA", Scientific American Books, ^7ew York; Birren et al. (eds) "Genome Analysis: A Laboratory Manual Series", Vols. 1-4, Cold Spring Harbor Laboratory Press, New York (1998); methodologies as set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659 and 5,272,057; "CeU Biology: A Laboratory Handbisbk", Volumes I-HI Celiis, J. E., ed. (1994); "Current Protocols in Immunology" Volumes I-ffl CoUgan J. E., ed. (1994); Stiles et al. (eds), "Basic and Clinical Immunology" (8th Edition), Appleton & Lange, Norwalk, CT (1994); Mishell and Shiigi (eds), "Selected Methods in Cellular Immunology", W. H. Freeman and Co., New York (1980); available immunoassays are extensively described in the patent and scientific literature, see. for example, U.S. Pat. Nos. 3,791,932; 3,839,153; 3,850,752; 3,850,578; 3,853,987; 3,867,517; 3,879,262; 3,901,654; 3,935,074; 3,984,533; 3,996,345; 4,034,074; 4,098,876; 4,879,219; 5.011,771 and 5,2S1,521; "Oligonucleotide Synthesis" Gait, M. J., ed. (1984); "Nucleic Acid Hybridization" Hames, B. D., and Higgins S. I, eds. (1985); "Transcription and Translation" Hames, B. D., and Higgins S. J„ eds, (19S4); "Animal Cell Culture" Fveshney. R. !., ed. (1986); "Immobilized Cells and Enz>TOes' IRL Press, (1986); "A Practical Guide to Molecular Cloning" Perbal, B,, (I9S4) and "Methods in Enzymology" Vol. 1-317, Academic Press; "PCR Protocols: A Guide To Methods And Applications", Academic Press, San Diego, CA il990); Marshak et al., "Strategies for Protein Purification and Characterization - A Laboratory Course Manual" CSHL Press (1996); all of which are incorporated by refer;;nce as if fully set forth herein. Other general references are provided throughout this document. The procedures \herein are believed to be well known in the art and are provided for the convenience of the reader. All the information contained therein is incorporated herein by reference- EXAMPLE 1 Alanine scan of the hlAPP basic amylodogenic unit - rational and peptide synthesis pancreatic amyloid is found in more thaji 95 % of type 11 diabetes patients- Pancreatic amyloid is formed by the aggregation of a 37 amino acid long islet amyloid polypeptide (LAPP, GenBank Accession No. gi:4557655), the cytotoxicity thereof being directly associated with the development of the disease. LAPP amyloid forraalion follows a nucleaiion-dependenl polymerization process, which proceeds hrough conformational transition of soluble ^LAPP into aggregated j3-sheets. Recently it has been shown that a hexapeplide (22-27) (NFGAIL, SEQ ID NO: 111) )f lAPP, also termed as the "basic amyloidogenic unit" is sufficient for the formation if P-sheet-containing amyloid fibrils [Konstantinos et al. (2000) J. Mol. Biol. :95:1055-!071]. To gain ihrther insight into the specific roie of the residues that compose "the basic aroyloidogenic unit", a systematic alanine scan was performed, Amino-acids ^ere replaced with alanine in order to specifically change the molecular interface of le peptides, without significantly changing their hydrophobicity or tendency to form -sheet structures, alanitie-scan was preformed in the context of the block that is nique to human LAPP (Pigure 3a). This block includes two serine residues that illow the NFGAIL motif in the fiill-length polypeptide. These eight amino-acid peptide sequences were used since the shorter peptides are hydrophobic and as s such less soluble. Figure 3b shows a schematic representation of the chemical structure of the wild-type peptide while Figure T-c indicates the amino-acid substitutions in the difTerent mulant peptides ihat were generated. Methods and Reagents - Peptide svTithesis was performed by PeptidoGenic Research & Co. Inc (Livemrorc, CA USA), The sequence identity of the peptides was confirmed by ion spray mass-spectromeiry using a Perkin Elmer Sciex API 1 spectrometer. The purity of the peptides was confirmed by reverse phase high-pressure hquid chromatography (RP-HPLC) an a C(^ colurrm, using a linear gradient of 10 to 70% acetonitrile in water and 0.1% trifluoroacetic acid (TFA). EXAMPLE 2 Kinetics of aggregation of lAPP peptide fragment and mutant derivatives as monitored by turbidity measurements To study self-assembly of the LAPP peptide derived fragments, aggregation and insolubilizalion kinetics were monitored using turbidity measurements at 405 nm. Kinetic aggregation assay - Fresh peptide stock solutions were prepared by dissolving lyophihzed form of thie peptides in DMSO, a disaggregating solvent, at a concentration of 100 mM. To avoid any pre-aggregation, fresh stock solutions were prepared prior to each and every experiment. Peptide stock solutions were diluted into assay buffer and plated in 96-weIl plates as follows: 2 \x\ of peptides stock solutions were added to 98 |il of 10 mM Iris pH 7.2, resulting in a 2 mM'final concentration of the peptide in the presence of 2% DMSO. Turbidity data was measured at 405 nm. A buffer solution including 2 % DMSO was used as a blank. Turbidity was measured at room temperature over several time points. Results - As shown in Figure 4a, wild-type peptide fragment (SEQ ID NO: I) showed an aggregation kinetic profile that was very similar to those previously reported for non-seeded hIAPP hexapeptide [Tenidis et al. (2000) J. Mol. Biol 295:1055-71]. Such a profile is strongly indicative of a nucSeatson-dependent polymerization mechanism [Jarrett and Lansbury (1992) Biochemistry 31:6865-70}. Following a lag-time of 20 minutes, wild type peptide self-assembled into insoluble iionis. feptide 03A (SEQ ID NO; 4) showed essentially the same profile as that of wild type peptide. The NIA peptide (SEQ ID NO: 2) mediated higher kinetics of aggregation, albeit with different kinetic profile as compared to that of wild-type peptide. Interestingly, the aggregation of NiA seemed to be less nucieaiion-dependent. Substitution of the isoieucine or leucine to alanine (peptides 15A, SEQ ID NO: 5 and L6A, SEQ ID NO; 6 respecli'.ely) reduced the kinetics of aggregation but did not abolish it compleleiy. Substitution of the phenylalanine residue to alanine (peptide F2A. SEQ ID N0:3) led to a total loss of peptide ability to aggregaie. The F2A peptide was completely soluble in the aqueous assay buffer. Altogether, kinetic aggregation studies of the amyloidogenic fragments suggested a major role to the phenylalanine residue in the process of amyloid formation by the lAPP active fragment. EX^iMPLE 3 Measuremeni of aggregate mean particle size While the turbidity assay provided an important estimate regarding the aggregation potential and kmetics of the various peptides, it did not provide information about the size of the actual aggregates formed. It will be appreciated that although the apparent hydrodynamic diameter of amyloid structures vanes due to irregularity of the amyloid structure, it may still provide a clear indication about the order of magnitude of the strucrore formed and present a quantitative criterion for :omparing the structures formed by the various peptides. Therefore, the average size of the aggregates, formed by the various peptides, vas determined using dynamic light scattering (DLS) experiments. Method - Freshly prepared peptide stock solutions at a concentration of iO nM were diluted in 10 mM Tris buffer pH 7.2 and further filtrated through a 0.2 pm ilter to a final concentration of 100 yM peptide and 1% DMSO. Particle size aeasurement was conducted with a laser-powered ALV-NIBS/HPPS non-invasive ackscattering instrument. Autocorrelation data was fitted using the ALV-TIBS/HPPS software to derive average apparent hydrodynamic diameters. Results - The average apparent hydrod\'namic diameters of the structures that 'ere formed by the various peptides are presented in Figure 5. Altogether, the apparent hydrodynaniic diameter of the structures formed by the various peptides seemed lo be consistent with the resuJls obtained fay ihe turbidity assay. As with the turbidity assay, the wild-type peptide and G3A peptide formed particles of very similar hydrod\Tiamic diameters- Smaller structures were observed with the derivative peptides: NIA, I5A and L6A. Thus, in accordance with the turbidity assay, the DLS e>;perimen'.s clear'.v illustrate that no large particles were formed by the F2A peptide under the indicated experimental conditions. EXAMPLE 4 Examination of aniyloidogenie performance ofm!d type peptide and derivatives through Congo Red (CR) binding assay Congo red (CR) staining combined with polarizalion microscopy was utilized to test amyloidogenicity of the peptides of the present invention. Amyloid fibrils in genera], and hbrilar LAPP in particular, bind CR and exhibit gold-green birefringence under polarized light [Cooper (1974) Lab. Invest. 31:232-8; Lansbury (1992) Biochemislry 31:6865-70}. Method and reagents - Peptide solutions incubated in a 10 mM Tris buffer (pH 7) for four days were dned on a glass microscope slide. Staining was effected by the addition of i mM CR in 10 mM Tris buffer pH 7.2 followed by a 1 minute incubation. To remove excess CR, slides were rinsed with double-distilled water and dried. Saturated CR solutions solubilized in 80% ethanol (v/v) were used for poorly aggregating peptides. In such cases, staining was effected without rinsing. Birefringence was determined using a WILD Makroskop m420 (x70) equipped with a polarizing stage. Results - Wild type, NlA and G3A peptides bound CR and exhibited the characteristic green/gold birefringence (see Figures 6g, 6a and 6e for normal field and Figures 6h, 6b and 6f for polarized light nnicroscopy, respectively). Peptides ISA and L6A, bound CR and exhibited rare but characteristic birefringence (Figures 6i and 6k for normal field and Figures 6j and 61 for polarized light, respectively). Peptide F2A (NAGAJL) showed no capability of binding CR (Figure 6c for normal field and Figure 6d for polarized light). Dried buffer solution stained with CR was used as a negative control (see Figures 6m and 6n for normal and polarized light, respectively). Interestingly, no significant difference in binding was observed for the negative control and the F2A peptide. To subslanliate the inability of F2A peptide to form fibrils, a peptide sohition incubated for 14 days was used in Ihe binding assay. Although some degree of aggregation was visually observed following two weeks of peptide "aging", CR staining showed no amyloid strucrure (results nol shown)- Under the same conditions wild-type peptide incubation resulted in signiiicant CR birefringence. EXi\fPLE 5 Ultrasiruciural analysis of the fibriilogenic peptide and mutants The fibriUogenic potential of the various peptides was assessed by electron microscopy analysis. Method - Peptide solutions (2 mM peptide in 10 mM Tris buffer pH 7.2), were incubated overnight at room temperature. Fibrils formation was assessed using ]0 p] sample placed on 200-mesh copper grids, covered with carbon-stabilized formvar film (SPI Supplies, West Chester PA), Following 20-30 seconds of incubation, excess fluid was removed and the grids were negatively stained with 2% uranyl acetate in water. Samples were viewed in a JEOL 1200EX electron microscope operating at SO kV. Results ~ To further characterize the structures formed by the various peptides, negative staining electron microscopy analysis was effected. In accordance with previous results, filamentous structures were observed for all peptides (Figures ?a-f) but F2A which generated amorphous fibrils (Figure 7b). Frequency of appearaiice of fibrils formed by the ISA and L6A peptides (Figures 7e and 7f, respectively) was lower in comparison to that of wild type (Figure 7d), Nl A, and G3A peptides (Figures 7a and 7c, respectively). Although the EM fields shov™ for peptides F2A, ISA and L6A, were rarely observed, the results presented by these images suppon the quantitative results presented in the previous sections and thus provide qualitative analysis of fibril morphology. The tangled net-like structures that were observed foe the wild-type, N1 A, and G3 A peptides could be explained by the fast kinetics of formation of these fibrils (see Example 2). More distinct structures and longer fibrils, albeit less frequent, were observed with peptides ISA and I,6A. These longer fibrils may be a result of a slower kinetics, which allow for a more ordered fibril organization. Taken together, (he qualitative results of the election microscopy and CR analyses strongly suggest thai Ihe phenylalanine residue in the hexaamyloid peptide is crucial for its amyloidogenic potential. EXUtPLE 6 Mapping recognition domains in the hIAPP basic amyloidogenic unit -rational and MBP-[APP fusion protein synthesis To syslematically map and compare potential recognition domains, the ability of hIAPP (GenBank Accession No. gi:4557655) to interact with an array of 2S membrane-spolted overlapping peptides that span the entire sequence of hlAPP (i.e., hlAPP,.!o, hIAPP;.,, ., hL\PP2g-37) was addressed [Mazor (2002) J. Mol. Biol, 322:1013-24]. Materials and Experimental Procedures Bacterial strains - E. coli strain TG-1 (Amersham Pharmacia, Sweden) was used for molecular cloning and piasmid propagation. The bacterial strain BL21 (DE3) (Novagen, USA) was used for protein overexpression. Engineering synthetic lAPP and MBP-IAPP fusion proteins - A synthetic DNA sequence of human lAPP modified to include a bacterial codon usage (SEQ ID NO: 58) was generated by annealing 8 overlapping primers (SEQ ID NOs. 50-57). PCR was effected through 1,0 cycles of I minute at 95 "C, one minute at 55 "C, and one minute at 72 "C. The annealing product was ligated and amplified using primers lAPPl (SEQ ID NO: 50) and IAPP8 {SEQ ID NO: 57). An MBP-IAPP (MBP GenBank Accession No. gi:265402l) fusion sequence was then constructed using the lAPP synthetic template, which was amplified using primer YAR2 {SEQ H) NO; 60) and primer YARl (SEQ ID NO. 59), thereby introducing a V8 Ek cleavage site and a Tiis)6 tag at the N-lerminus of lAPP. The two primers included a Noi I and an i^co I ;loning sites, respectively. The resultant PCR product was digested with Nco I and Vol I and ligated into the pMALc2x-NN expression vector. The pMALc2x-NN expression vector was constructed by cloning the polylinker site of pMALc-NN'^ into iMALc2x (New England Biolabs, USA) [BACH (2001) J. Mol. Biol. 312:79-93], protein expression and puri/itu„u„ - £. coli BL21 cells transformed with expression plasinid pMALc2x-lAPP encoding MBP-IAPP under the strong Ptac promoter were grown in 200 ml of LB medium supplemented with lOO ^g^^^l ampicillin and 1% (W/V) glucose. Once reaching an oplicai density of AQ,-.) _- 0.8, protein expression u'as induced wit]-. 0,1 orQ.i imM EPTG al BQ^C for 3 hours (h). Ceil extracts were prspared in 20 mM Tnc-HCI (pH 7.4), 1 mM EDTA, 200 mM NaCl and a protease inhibitors cocklai! (Sigma) using a freeze-thaw followed by a brief sonication as previously descnbed [Gazit (1999) J. Biol. Chem. 274:2652-2657]. Protein extracts were clarified by cer,mfugation at 20,000 g and stored at 4° C, NIBP-LAPP fusion protein was purilled by passing the extract over an amylose tesia column (New England Biolabs, USA) and recovered by elution with 20 mM maltose in the same buffer. Purified MBP-LAPP was stored at 4 "C. Protein concentration was determined using the Pierce Coomassie plus reagent (Pierce, USA) with BSA as a standard. \fflP and MBP-LAPP protein fractions were anal>'zed on SDS/12 % polyacrylamidc gels, which '.vcre stained with GelCode Blue (Pierce, USA). To study whether the disulfide bond in the MBP4APP are oxidized, purified MBP and MBP-LAPP proteins were reacted with 5 equivalents of N-iodoacet>'l-N"-(S-sulfo-1-naphthyl) elhylenediamine (lAED.-VNS) (Sigma, Rehovot, Israel) for overnight at room temperature in the dark. Free dye was separated from labeled protein by gel filtration chromatography on a QuickSpin G-25 Sephadex column. MBP and MBP-L^PP fluorescence was then determined. Only small fluorescence labeling was detected (on average less than 0.1 probe molecules per protein molecules) and there was no significant difference between the labeling of MBP and MBP-IAPP, which suggested that the disulfide bridge in the expressed L^P molecules was predominantly oxidized. Results Expression and purification of recombinant MBP-IAPP - Since previous attempts to express the intact hLAPP in bacteria were unsuccessful, the proteiri was expressed as an MBP fusion, which protected hLAPP from undesirable aggregation during expression [Bach (2001) J, Mol. Biol. 312:79-93]. Synthesis of the fusion protein was effected using a bacterial codon usage as shown in Figvire 8a. The resulting fusion sequence was cloned into pMALc2x-NN as shown in Figure 8b and * / iiiirouuceQ mxo ii- con tiLi!(DE3). Growth conditions, cell extract preparation and protein purification were effected as described hereinabove. IPTG induction resulted in the accumulation of high levels of MBP-LVPP in the soluble fraction with less then 5% of the MBP-IAPP fusion protein was found in the insoluble fraction of the cell extract (data not shown). Aliquots from typical purification steps of MBP and MBP-IAPP are sfiouTi in Figure 9. As sho'ATi, the 48 kDa MBP-IAPP accumulated to 25% of the total soluble protein as calculaied by densitometric scanning of GelCode Blue-stained SDS/Polyacp.iamide gels. When induced a! 30'C in a shake flask (A^oo = 2.0), MBP-IAPP accumulaisd as soluble protein in the cytoplasm at a level of about 150 mg/1 of cell culpjre. Despite losses dunng purification, MBP-LAPP was purified to near-homogeneitv' at a vield of SO mg/1 of cells. For future application and convenient homogeneity purification of LAPP, in addition to the factor Xa cleavage site for removal of the MBP tag, an additional His-Tag was also included (Fig'jre 8b). The His-Tag could be removed by Ek VS cleavage at the N-terminal Lys residue of the lAPP sequence, resulting in the release of wild type lAPP, EX-iMPLE 7 Identification of molecular recognition sequences in the hLiPP polypeptide lAPP peptide array construction - Decamers corresponding to consecutive overlapping sequences of hIAPPi.37 SEQ ED NOs. 61-88) were synthesizes on a cellulose membrane matrix using the SPOT technique (Jerini AG, Berlin, Germany). The peptides were covalentjy bound to a Whatman 50 cellulose support (Whatman, Maidstone, England) via the C-terminal amino-acids. N-terminal acetylation" was used for peptide scanning because of higher stability to peptide degradation, and better representation of the native recognition motif Peptides Synthesis - Peptide synthesis was effected using solid-phase synthesis methods perfomied by Peptron, Inc. (Taejeon, Korea). Correct identity of the peptides was confirmed by ion spray mass-spectrometry using a HP 1100 series LC/MSD [Hewlett-Packard Company, Palo Alto, CA]. The purity of the peptides was confirmed by reverse phase high-pressure liquid chromatography (RP-HPLC) on a Cig column, using a 30 minute hnear gradient of 0 to 100%. acetonitrile in water and 0.1% trifluoroacelic acid (TF.A) at flow rate of I ml'min. Binding studies - The cenu!o5e peptide array was initially blocked with 5 % (VAO non fat milk in Tris buffered saline (TBS, 20 mM Tris pH 7.5 , 150 mM NaCI). Thereafter, cellulose membrane was incubated in the presence of 10 \is^'m\ MBP-IAPP^37 at 4°C for 12 h in the same blocking buffer. The cellulose membrane was then washed repeatedly with 0.05 % Tween 20 in TBS. ND3P-L\PPi.;7 bound to the cellulose membrane was detected with an anti MBP monoclonal antibody (Sigma, Israel). HRP-conjugated goat anii mouse antibodies (Jackson Laboratories, L'SA) were used as a secondary antibody. Immunoblots were developed using ihe Renaissance western blot Chemiluminescence Reagent (N"EN, USA) according to Manufacturer's instructions and signal w'as quantified using densitometry-Regeneration of the cellulose membrane for reuse was carried out by sequential washing with Regeneration buffer I including 62.5 mM Tris, 2% SDS, 100 Mm 2-mercaptoethanol, pH 6.7, and Regeneration buffer IT including 8 M urea, "l°'o SDS, 0.1% 2-mercaptoethanoi. Efficiency of the washing steps was monitored by contacting the membrane with the chemiluminescence reagent, as described. Results Idenliftcaiion of binding sequences in the lAPP polypeptide - To identify structural motifs in the lAPP molecule that mediates the intermolecular recognition between hLAPP molecules, 28 possible overlapping decamers corresponding to amino acids 1-10 up to 28-37 of the hlAPPi-]? molecule were synthesized on a cellulose membrane matrix. Cellulose membrane-bound peptides were incubated with MBP-hL\PP].37 overnight Following washing of the cellulose membrane in a high-salt buffer, immunoblots on the cellulose membrane were analyzed and binding was quantified by densitometry {Figure 10b). It will be appreciated that the measured binding is semiquantitative, since peptide coupling efficiency during synthesis can vary. As shown in Figures JOa-b, a number of peptide segments exhibited binding to MBP-LAPP; An amino acid sequence localized to the center of the LipP polypeptide (i.e., hIAPp7-i6 to hLAPPjj.zi) displayed die most prominent binding to MBP-W.-VPFu 37-. Another binding region was identified at the C-temiinal part of LAPP (hlAPPig.za to hLAPP2i.3D), although binding in this case was considerably less prominent; A third binding spot was located to the N-terminal part of LAPP (hL\PP2-ii), however, no typical distribution around a central motif was evident in this case, suggesting that this . .- m 1 / NtLVH 15-19 18 FLVHS 15-18 19 FLVH Materials and Experimental Procedures Kinetic Aggregation Assay - freshly prepared peptide stock solutions were generated by dissolving the lyophilized ibrm of the peptides in dimethyl sulfoxide (DMSO) al a concenlration of 100 mg,'ni!. To avoid any pre-aggregalion, fresh slock solutions were prepared for each experiment. Peptide stock solutions were diluted into the assay buffer in enzynie-linixd immunosotbent assay (ELISA) plate wells as follows: 8 JJL of peptide stock solutions were added to 92 pL of 10 mM Tris, pH 7.2 (hence the final concentration of the peptide was 8 mg/mi in the presence of S% DMSO). Turbidity data were collected at 405 nm. Buffer solution containing the same amount of DMSO as the tested sarnples was used as blank, which was subtracted from the results. Turbidity was measured continuously at room temperature using THERMOma.x ELISA plate reader (^Eolccu!ar Devices, Sunny\'ale CA). Results Turbidity assay was performed in-order to determine the ability of the various peptides (Table 3) to aggregate in an aqueous medium. Fresh stock solutions of the different peptide fragments were made in DMSO, and then diluted into a Tris buffer solution and turbidity, as a hallmark of protein aggregation, was monitored for two hours. As shown in Figure U, the peptides NFLVHSS, FLVHSS and FLVHS exhibited high turbidity. It will be appreciated that the lag-time, as was previously reported for amyloid formation by the NFGAIL short peptide [Tenidis (2000) Supra], is very short or lacking at all and thus could not be detected under these experimental conditions, however the aggregation kinetic profiles were similar to those obtained for the hexapeptide hIAPp2;.27 (NFGAIL). On the other hand, the peptide NFLVHSSNN exhibited very low turbidity, while NFLVH and FLVH have shown almost no turbidity at all. Even after significantly longer incubation no significant turbidity was observed with the latter two peptides. The lack of amyloid fibrils formation may be due to electrostatic repulsion of the panially charged histidine residues. EXAMPLE 9 Examination of hiAPP peptide amyloidogenic through Congo Red (CR) binding assay Congo red (CR) staining combined '.vith polarization microscopy was utilized to test amyioidogenicity of the peptides or'the present invention. Amyloid fibrils bind CR and exhibit gold'green birefringence under polarized light [Puchtler (1966) J. Histochem. C>1ochem. 10:355-3641. Materials and Experimental Procedures Congo Red Staining and Birefringence - A 10 )iL suspension of S mg;'ral peptide solution in 10 mM Tris buffer, pH 7.2 aged for at least one day was allowed to dry overnight on a glass microscope slide. Staining was performed by the addition of a 10 )iL suspension of saturated Congo Red (CR) and NaCl in 80% ethanol (v/v) solution as previously described [Puchller (1966) Supra]. The solution was filtered via 0.45 pm filter. The slide was then dried for few hours. Birefringence was detennined with a SZX-12 Stereoscope (Olympus, Hamburg, Germany) equipped with cross polarizers. Results Congo Red Staining and Birefringence- In order to determine any possible amyloidal nature of the aggregates formed at the turbidity assay (see Example 8), a CR birefringence assay was performed. Peptide fragments were tested for amyloidogenecity by staining with CR and examination under a light microscope equipped with cross-polarizers. Consistent with the kinetic assay results, and as shown in Figures 120b-c and 12e, the peptides NFLVHSS, FLVHSS and FLVHS exhibited a typical birefringence. On the other hand, peptides NFLVHSSNN, NFLVH and FLVH exhibited very weak birefringence or no birefringence at all (Figures 12a, I2d and 12f). Peptide NFLVHSSNN exhibited a weaker characteristic birefringence 3^igure 12a). T he peptide I^ffLVH exhibited a powerfiil smear of birefringence at the :dges of the sample (Figure 12d). The peptide FLVH exhibited no birefringence 'Figure 121)- In order to test whether the FLVH peptide did not form amyloid fibrils iue to a long lag-time, a sample of five days aged peptide solution was examined. The same peptide was also tested in aqueous solution and at very high concentrations 10 mg/ml), however no Birefringence was detected in all cases indicating the peptide am not lorm amyloid (data not shoum)- EXAMPLEIO UltrastrucUiral analysis of the ftbrillogenic hIAPP peptides TTie fibriilogenic potential of the vanous peptides was assessed by electron microscopy analysis. Materials and Experimental Procedures Transmission Electron Microscopy - A 10 tiL sample of 8 ni^/'ml peptide solution in 10 OLM Tris buffer, pH 7.2 aged for at least one day was placed on 400-mesh copper grids (SPI supplies, West Chester PA) covered by carbon-stabilized Formvar film. Following I minute, excess tluid was removed, and the grid was then negatively stained with 2% uranyl acetate in water for another two minutes. Samples were viewed in a JEOL 1200EX electron microscope operating at SO kV. Results To further characterize the structures formed by the various peptides, negative staining electron microscopy analysis was effected. In accordance with previous results, all peptide fragments exhibited fibnilar structures except the FLVTi peptide in which only amorphous aggregates were found (Figures 13a-f). ^^FLVF^SSNN peptide exhibited long thin coiling filaments similar to those formed by the tiill-length peptide as described above (Figure 13a). Peptides NFLVHSS, FLVHSS, FLVHS exhibited laige broad ribbon-like fibrils as described for the NFGAIL fragment [Tenidis (2000) Supra., Figures 13c-e, respectively]. The fibrils formed by NFLVH peptide were thin and short and could be considered as protofilaments rather than filaments. "Their appearance was at much lower frequency, and the EM picture does not represent the general fields but rather rare events (Figure I3d). As shown in Figure !3f, the FLVH peptide mediated the formation of amorphous aggregates. EXAMPLE 11 Secondary structure analysis of hIAPP peptide fragments Fourier transform infrared spectroscopy (FT-IR) was effected to determine the secondary stracture of the hIAPP amyloidogenic peptide fibrils and the non-fibrillar peptides. lYiaienals and txperimenlal Procedures Fourier Transform Infrared Spectroscopy - Inirared spectra were recorded using a Nicolet Nexus 470 FT-tR spectrometer with a DTGS detector Samples of aged peptide solutions, taken from turbidity assay, were suspended on a CaF; widows (Sigma)-pi3le and dried by vacuum. The peptide deposits were resuspended with double-distilled water and subsequently dried to form thin films. The resuspension procedure was repeated U\-ice to ensure maximal hydrogen to deuterium exchange. The measurements were taken using a 4 cm' resolution and 20O0 scans averaging. The transmiltance minima values were determined by the OMNIC analysis program (Nicolet). Results FT-IR studies - As shown in Figure 14a-f, al! the fibrillar peptides exhibited FT-ER spectra with a well-defined minimum bands typical for P-sheet sbmcture around 1620-1640 cm"'. On the other hand the spectrum of the tetrapeptide FLVH that has no appearance for fibrils according to the other methods, is typical for a random coil structure. The NFLVHSSNN peptide spectrum exhibited a transmittance minimum at 1621 cm"' indicating a large 0 -sheet content, as well as minima at 1640 cm"' and 1665 suggesting presence of non- p structures. Another minor minimum was observed at 1688 cm' indicative for anti-parallel P-sheet (Figure Ma). The NFLVHSS peptide spectrum exhibited major minimum band at 1929 cm"' 1675 cm"', this spectrum is classical for an anti-parallel p -sheet structure (Figure 14b). A similar spectrum was observed for the peptide FLVHS with a major minimum at 1625 cm' and a minor minimum at 1676 cm"' (Figure 14e). The spectrum of FLVHSS peptide showed also a major miiumum at 1626 cm"'. The spectnim had also some minor minima around 1637-1676 cm"' but those were shaped more like noise than signal (Figure i4c). The spectrum of NFLVH peptide showed a minimum at 1636 cm' which was also indicative of p-sheet, however, in comparison with the other spectra, this band was shifted which could indicate presence of non- p stroctures, as well as observed minima It 1654 cm' and 1669 cm' (Figure 14d). By contrast, the FLVH peptide spectrum ;xhibited no minimum al 1620-1640 cm"', but showed multiple minima around 1646-675 cm" typical to random coil structure (Figure 14f)- To study whether the FLVH tetrapeptide could not form amyloid fibrils at all ui ijic unueieciaoie imnis lonnation was a result of a slow kinetics, a solution of tVie peptide at the same experimental conditions was incubated for two months and the existence of fibrils was tested. However, no evidence for amyloid fibril formation was detected using EM micioscopy, CR siaining, or FT-IR spectroscopy. TViese results may suggest that tetrapeptides are incapable of forming fibrils due to energetic consideration. Thai is, the energetic contribution of the stacking of a strand composed of three peptide bonds is lower than the entioDic cost of oHgomerization. Taken together, the ultrastrucrural observations are consistent with the findings as determined by the hirbidity and Congo red birefringence assays. All together the experimental data identified a novel pentapq^tide element within the hIAPP peptide, the FLVHS peptides, which has strong amyloid forming capability. Interestingly, an NFLVn peptide found in the same centra! domain of the hIAPP polypeptide was found to be amyloi do genie however, the ability thereof to forra fibrils was somehow inferior. EXAMPLE 12 Identification of the minimal amyloidogeiiic peptide fragment ofMedin Background Medin (GenBank Accession No. gi:5I74557) is the main constitute of aortic media! amyloid deposits [Haggqvist (1999) Proc. Natl. Acad. Sci. USA. 96:8674-8669]. Previous studies found aortic medial amyloid in 97% of the subjects above the age of 50 [Mucchiano (1992) Am. J. Pathol. 140:811-877]. However, the pathologica] role of those amyloid deposits is still unknown. It was suggested'that these amyloid play a role in the dimmished elasticity of aortic vessels that is related to old age [Mucchiano (1992) Supra; Haggqvist (1999) Supra]. While the study clearly identified a tryptic peptide NFGSVQFV as the medin amyloidogenic peptide, the minimal sequence of the peptide that is still amyloidogenic and the molecular determinants that mediate the amyloid formation process were not determined. Such information is critical for true understanding of the fibrillization process in the specific case of Medin but also as a paradigm for the process of amyloid fibrils formation in general. 1 he rmniraal active fragment of Medin was determined using functional and strucforal analyses of imncated anaicgues derived from the published oclapcptide [Haggqvist (1999) Supra]. Materials and Experimental procedures Peptide synthesis is described in Example 7. Table 4 below illustrates the sfjdied peptides- Result^ !n ordei to get Sunhcr insights into the structural elements of Medin that retain the molecular information needed to mediate a process of molecular recognition and se!f-assembiy, the ability of short peptide fragments and analogues of Medin to form amyloid fibrils in viiro was studied. Figure 15a shows a schematic representation of the chemical structure of the largest peptide fragment studied- EXAMPLE13, Kinetics of aggregation of Medin-derived peptide fragments Turbidity assay was efiected as described in Example 8. In order to get first insights regarding the aggregation potential of the various Medin derived peptides, turbidity assay was performed. Freshly made stocks of the amyloidogenic octapeptide and truncated analogues thereof were prepared in DMSO. The peptides were than diluted to aqueous solution and the turbidity was monitored by following the absorbance at 405 mn as a function of time. As shown in Figure 16a, the NFGSV penlapeptide exhibited the highest degree of aggregation witfiin minutes of incubation. Physical examination of the solution indicated that the peptide formed a ge! stuicture. The kinetics of aggregation of the KFGSVQV octapeptide was too fast to be measured since turbidity was already observed immediately with the dilution into aqueous solution (Figures 16a-b). Similar fast Rinetics were also observed with the GSVQ tetrapepllde. The tnincated NFGSVQ, FGSVQ, and FGSV peptides showed a gradual increase in turbidity over-30 minutes (Tigure !6b) which was followed by a slight decrease, which could be explained by sedimentation of large aggregates. Altogether, such kinetics and turbidity values were similar to those previously observed with amyioidogenic peptides of similar size (Azriel and Gazit, 2001). EX-LMPLE 14 Ultraslruaural analysis of Med'ut-derived peptide fragments Electron microscopy analysis was effected as described in Example 10. The fibrillizatioa potential of Medin-derived peptide fragments was effected by electron microscopy (EM) using negative staining. Stock solutions of the peptide fragments were suspended and aged for 4 days. Fibrillar structures were clearly seen in solutions that contained both the NFGSVQFA octapeptide (Figure 17a) and the truncated NFGSVQ (Figure 17b ). hi both cases the structures were similar to those observed with much longer polypeptides, such the LAPP and the p-amytoid (Ap) polypeptides. The shorter gel-forming NFGSV pentapcptide did not form a tvpical amyloid structure but a network of fibrous structures (Figure 17c), It should be noted that fibrous networks were recently observed upon the gelation of the glutathione peptide [Lyon and Atkins, (2001) J. Am. Chem. Soc. 123:4408-4413], No typical fibrils could be detected in solutions that contained the FGSVQ pentapeplide, the GSVQ tetrapeptide, or the FGSV tetrapeptide in spite of extensive search. While in the case of the FGSVQ peptide (Figure 17d) somewhat fibriliar and ordered stru'cture could be seen, although significantly different than those formed by typical amyioidogenic peptide), in the case of the GSVQ and the FGSV peptides, no fibrillar stnictures couSd be foimd (Figures 17e and 17f, respectively). EXAMPLE 15 Examination of amyioidogenic performance of Medin-derived peptides through Congo Red (CR) binding assay CR staining was effected as described in Example 9. A CR staining was effected to determine whether the structures fonned by the various Medin-derived peptides show a typical birefringence. As shown in Figure 18b, the NFGSVQ hexapeptide bound CR and exhibited a characteristic bright and strong green-gold birefringence. The NFGSVQFV octapeptide also exhibited significant birefringence (Figure 18a). although less typical than that observed with the hexapeptide. The gel-forming NFGSV peptide deposits exhibited very )ow degree of birefringence (Figure 18c). The FGSVQ and FGSV peptide showed no birefringence upon staining with CR {Tigurcs ISd and ISf, respectiveiy). There was clearly no significant difference beKvcen ihose two peptides and a negative control (i.e., buffer solution with no peptide) Interestingly, unexpected high level of birefiingence was observed with the GSVQ lefrapeptide (Figure l8e), while the morphology of the structures formed therefrom (Figure ISe) was clearly different from that of amyloid fibrils, indicating thai these structures may have a significant degree of order that is reflected in strong birefringence. EXAMPLE 16 The effect afphenylalanine substitution on the self-assembly ofMedin T elucidate a possible role for the phenylalanine residue in the process of amyloid fibrils formation by the minimal amyloid-fonmmg hexapeptide, the phenylalanine amino acids was replaced with an alanine. The alanine-substituted peptide was prepared and examined in the same way as described for the various fragments ofMedin. As shown in Figure 19a, a significantly lower turbidity was observed with the alanine-substituted peptide as compared to the wild-type hexapeptide. When aged solution of the NAGSVQ peptide was visualized by EM, no clear fibrillar structures could be detected (Figure 19b). This is in complete contrast to the high abundance fibrillai structures seen with the wild-type peptide (Figure 17b). Furthermore, ihe struchjres that were visualized did not show any degree of order as observed with the NFGSV and FGSVQ peptides as described above. Figures 17c-d, but were very similar to the completely non-frbrillar structures as were observed with the FGSV tetrapeptide (Figure I7e). friteresungly, some de^ee of birefringence could still be detected (Figure 19c) with the alamne-substituted peptide (as was observed with the GSVQ peptide, Figure !8e). These results raise further doubts regarding the use of CR staining as a sole indicator of amyloid formation [Khurana (2001) J- Bio). Chem. 276;22715-2272n. Altogether these results show thai the truncated fragment of Medin which is capable of forming amyloid fibrils is the hexapeptide NFGSVQ (SEQ ID NO: 2!), although a shorter pentapepUde fragment, NTGSV (SEQ ID NO: 22), exhibited a network of fibrous structures whicli were not typical of amyloids. The amyloid forming NFGSVQ hexapeplide is noticeably similar to the minimal amyloidogenic fragment of the islet amyloid polypeptide (L-VPP, see Examples 1 -5). Taken together, the results are consistent with the assumed role of stacking interactions in the self-assembly processes that lead to the formation of amyloid fibrils and the suggested correlation between amyloid fibrils and |3-helix structures. EX.-iMPLEl7 Identification of {he minimal amyloidogenic peptide fragment of human Calcitonin Human Calcitonin (hCT, GenBank .Accession No. gi:179S80) is a 32 amino acid long polypeptide hormone that is being produced by the C-cells of the th>Toid and is involve in calcium homeostasis [Austin and Health (1981) N. Engl. 3. Med. 304:269-278; Copp (1970) Annu. Rev. Physiol. 32:61-86; Zaidi (2002) Bone 30:655-663]. Amyloid fibrils composed of hCT were found to be associated with medullary carcinoma of the thyroid [Kedar (1976) Isr. J. Sci. 12:1137; Berger (1988) Arch. A. Pathol. Anat. Histopathoh 412:543-551; Aivinte (1993) J. Bioh Chem. 268:6415-6422]. Interestingly, synthetic hCT was found to form amyloid fibrils in vitro with similar morphology to the deposits found in the thyroid [Kedar (1976) Supra; Berger (1988) Supra; Arvinte (1993) Supra; Benvenga (1994) J. Endocrinol. Invest. 17-.U9-122; Bauer (1994) Biochemistry 33:12276-12282; Kanaon (1995) Biochemistry 34:12138-43; Kamihara (2000) Protein Sci. 9:S67-877]. The m vitro process of amyloid formation is affected by the pH of the medium [23]. Electron microscopy experiments have revealed that the fibrils formed by hCT are approximately 80A in diameter and up to several micrometers in length. The fibrils are often associated with one another and in vitro amyloid formation is affected by the pH of the medium [Kamihara (20O0) Supra.]. Calcitonin has been used as a drug for various diseases including Paget's disease and osteoporosis. However, the tendency of hCT to associate arid form amyloid fibrils in aqueous solutions ai ph>-siological pH is a significant limit for its efficient use as a drug [Austin (1981) Supra; Copp (1970) Supra; Zaidi (2002) Supra]. Salmon CT [Zaidi (2002) Supra], &,t clinically used alternative to hCT, causes immunogenic reaction in treated patients due to low sequence homology. Therefore, anderstanding the mechanism of arr.yloid formation by hCT and controlling this process is highly important not only in the context of amyloid formation mechanism 3Ut also as a step toward improved therapeutic use of Calcitonin. Circular dichroism (CD) studies havs shown that in water monomeric hCT has ittle ordered secondary structure at room temperature [.Arvinte (1993) Supra], however, studies of hCT fibrils using circular dichroism, fluorescence, and infrared ;peclroscopy revealed that fibrillated hCT molecules have both a-helical and j3-shcel lecondary structure components [Bauer (1994) Supra]. NMR spectroscopy studies lave shown that in various structure promoting solvents like TFE/H:0, hCT adopts an jnphiphilic a-helical conformation, predominantly in t!ie residue range 8-22 Meadows (1991) Biochenriistry 30-.n47-\254; Motta (1991) Biochemistr/ 30-.10444-0450]. In DMSO/H;0, a short double-stranded antiparallel [J-sheet form in the entral region made by residues 16-21 [Motta (1991) Biochemistry 30:2364-71]. Based on this structural data and the proposed role of aromatic residues in the rocess of amyloid formation, the present inventor has identified a short peptide ragment, which is sufficient for mediating Calcitonin self-assembly [Reches (2002) J. liol. Chem. 277:35475-80]. The studied peptides - Based on the previously reported susceptibility of nyloid formation to acidic pH [Kanaori (1995) Supra], it was suggested that sgatively-charged amino-acids, which undergo protonation at low pH, may play a 2y role in the process of amyloid formation. The only negatively-charged amino-acid I hCT is Asp'^ (Figure 20a). Furthermore, a critical role for residues Lys'^ and Phe' I the oiigomerization state and bioactivity of hCT was recently shov/n [Kazantzis :69) Eur, J. Biochem. 269:780-91]. Together with the occurrence of two lenylalanine residues in the region focused the structural analysis of the nyloidogenic determinants in hCT to amino acids 15-19- Figure 20b shows a si-iiciuuiii; icpic^cuLaLiuii uj uic tnemicai structure ol tne longest peptide and table 3 beiow, indicates the various peptide fi^gments that were used in the shidy. Table 5 Amino acid cooniinales on hCT Peptide sequence SEQ ID NO: 15-19 HHj-OFNK'F-CGOH 27 16-19 tlH;- fMK'F-CCCH 28 15-18 NH;-:'FNK -CCOH 29 15-17 tiH.-Drri -cc:-H 30 F>A 15-19 :iH;-DANKF-CCOH 31 EX^iMPLE IS Vltrasiructural analysis of Calcilonin-derivcd peptide fragments Electron microscopy analysis was effected as described in Example 10, The fibrilHzation potential of Calcilonin-derived peptide fragments was effected by electron microscopy (EM) using negative staining. Stock solutions of the peptide fragments were suspended in 0.02M NaCl, O.OIM Tris pH 7.2, aged for 2 days and negatively stained. Fibnllar structures, similar to those formed by the fall-length polypeptide [Arvinte (1993) Supra; Benvenga (1994) Supra; Bauer (1994) Supra; Kanaori (1995) Supra; Kamihara (2000) Supra], were clearly seen with high frequency in solutions that contained the DFNKF penlapeptide (Figure 21a). The shorter DFNK tetrapeptide also formed fibrillar structures (Figure 21b). However, the structures fonmed were less ordered as compared to those formed by the DFNKF pentapqjtide. The amount of fibrillar structures formed by DFNK was also lower as compared to the DFNKF peptapeptide. No clear fibrils could be detected using solutions that contained the FNKF tetrapeptide and the DFN tnpepttde, in spite of extensive search. In the case of the FNKF tetrapeptide only amorphous aggregates could be found (Figure 21c). The DFN tripeptide formed more ordered structures (Figure 21d) that resembled the structure formed by gel-forming tripeptide [Lyon (200!) Supra]. To study whether the FNTCF tetrapeptide and the DFN tripeptide peptide cannot form fibrils whatsoever or the observation is a result of slow kinetics, a ;olution of the peptides at the same experimental conditions was incubated for two ■veeks. Also in this case no clear fibrillar structures could be detected (data not jhown). Examination of amyloidogenic performance of Calcitonin-derivedpeptides through Congo Red (CR) binding as^ay CR staining was eft~ected as described in Example 9- A CR staining was effected to determine whether the structures formed by the various hCT-derivcd peptides show a t>p:cal birefringence. As shown in Figures 22a-d, all the studies peptides showed some degree of birefringence. However, the green birefringence, which was obscr.ed with the DFNKF-penlapeptide was clear and strong (Fig'jre 22a). The level of birefringence that was observed with the other peptides was lower but significant since no birefringence could be detected using control solutions which did not contain the peptides. The lower level of birefringence of the DFNK tetrapeplide (Figure 22b) was consistent with the lower extent of librillization as observed using EM (Figure 21b). It will be appreciated, though, that the birefringence observed uith the FNKF letrapeptide and the DFN tripeptide might represent some degree of ordered structures [Lyon (2001) Supra]. EXAMPLE 20 Secondary structure of the aggregated hCT-derived peptides FT-IR spectroscopy was effected as described in Example 11. Amyloid deposits are characteristic of fibrils rich with P-pleated sheet itrucluies. To get a quanthative information regarding the secondary structures thai vere formed by the various peptide fragments FT-IR spectroscopy was used. Aged )eptide solutions were dried on CaF: plates forming thin films as described in ixample U. As shown in Figure 23, the DFNKF pentapeptide exhibited a double ninima (at 1639 cm' and 1669 cm') an amide I FT-IR spectrum that is consistent vith anti-parailei P-sheet stmcture and is remarkably similar to the spectrum of the myloid-forming hexapeptide fragment of the islet amyloid polypeptide [Tenidis 2000) Supra]. The amide I spectrum observed with the DFNK tetrapeptide (Figure 3) was less t>T?ical of a p-sheet structure. While it exhibited a minimum at 1666 m-1 that may reflect an anti-parallel p-sheet it lacked the typical minimum around 620-1640 cm' that is typically observed with p-sheet structures. The FNKF 3trapeptide exhibited a FT-IR spectrum that is typical of a non-ordered structure (Figure 23) and is similar to spectra of the short non-amytoidogenie fragments of the islet amyloid polypeptide [Tenidis (2000) Supra]. The DFN tripeplide exhibited a double minima (at 1642 cm' and 1673 cm'\ Figure 23) amide I FT-IR speciaim that is consistent with a mixture of p-sheet and random structures. This may further indicate that the structures observed by EM visualization may represent some degree of ordered structure composed of predominantly p-sheet structural elements. EXAMPLE 21 The effect of phenylalanine substitution on the self-assembly of Calciionin- derived peptides Ln order to gel insight into a possible role for the phenylalanine residues in the process of Calcitonin self-assembly, the phenylalanine amino acids were replaced with alanine in the context of the pentapeptide (SEQ ID NO: 31). When aged solution of the DANKF pentapeptide was visualized by EM, no clear fibrillar str\icttires could be detected (Figure 24a). Structures that were visualized exhibited some degree of order (as compared to the amorphous aggregates seen with the FNKF tetrapeplide), however, no green-gold birefringence could be observed (Figure 24b). The FT-IR spectrum of the DANKA pentapeptide was similar to that of the FNKF tetrapeptide and other short non-amyloidogenic peptide, typical of non-ordered structures [Tenidis (2000) Supra]. Taken together, the effect of the phenylalanine to alanine substitution is very similar to the effect of such a change in the.context of a short amyloid-forming fi-agment of the islet amyloid polypeptide [Azriel (2001) Supra]. Altogether, the ability of an hCT-derived pentapeptide (SEQ ID NO: 27) to form well-ordered amyloid fibrils was demonstrated. The typical fibrillar structure as seen by electron microscopy visualization (Figure 21a), the very strong green birefringence upon staining with CR (Figure 22a), and the typical anti-parallel p-sheet structure (Figure 23a), ail indicate that the DFNKF pentapeptide is a very potent amyloid forming agent. Other pentapeptides capable of self-assembling were shov^Ti in hereinabove. Yet, in terms of the degree of birefringence and electron microscopy morphology, the hCT fragment seems to be the pentapeptide with the highest amyloidogenic potential similar to the potent amyloidogenic fragment of the p-amyloid (AP) polypep''^' fr\.T:TrAT: rD.,i;,^^K orxccw D;--V...~:-._. --n.n-no ^.^^ It is possible that electrostatic interactions between the opposing charges on the lysine and aspartic acids direct the formation of ordered antiparallel stnichire. hiterestingiy, the DFNK polypeptide exhibited a significantly lower amyloidogenic poiential as compared to the DFNKF peptide, it is possible that a pentapcplide is a lower limit for potent amyloid former. This is consistent with recent results that demonstrate that nvo pcntapeptides of L-VPP, N'FLVH anc FLVHS, can form amyloid fibnls, but their common denominator, the letrapeptide FLVH, could not fonn such fibrils (see Examples 1-5). EXiMPLE 22 [dentificstion of an amyloidogenic peptide from Lactolransfsrrin Amyloiti fibhl formation by lactotransferrin (GenBank Accession No. gi:248952SO) is associated familial subepithelial corneal amyloid fomialion (Sacchettini and Keliy (2002) Nat Rev Drug Discov 1:267-75]. Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic features of a Lactotransferrin-derived peptide, LFNQTG (SEQ ED NO: 52) were studied. Materials and Experimental Procedures - Described in Examples 7 and 10. Results ~ To characterize the ability of the Lactotransferrin-derived peptide to form fibrilar supramolecular ultrastructures, negative staining electron microscopy analysis was effected. As shown in Figure 25,\under mild conditions, filamentous strucmres were observed for the selected peptide, suggesting that LFNQTG of Lactotransfemn is important for the polypeptide self-assembly. These results further substantiate the ability of the present invention to predict amyloidogenic peptide sequences, E7iAMPLE23 Identificaiion of an amyloidogenic peptide from Serum amyloid A protein Fragments of Serum amyloid A proteins (GenBank Accession No. gi:I34167) were found in amyloid-sfate in cases of Chronic inflammation amyloidosis (Westermark et al. (1992) Biochem. Biophys. Res. Commun. 182: 27-33). Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic features of a Serum amyloid A protein-derived peptide, SFFSFL {SEQ ID NO: 33) were studied. Materials and Experimental Procedures - Described in Examples 7 ard iO. Results - To characterize the abilit>- of the Serum amyloid A protein-derived peptide to form fibrilar supramolecular uicastructures, negative staining electron microscopy analysis was effected. As showTi in Figure 26, under mild conditions, filamentous structures were observed for the selected peptide, suggesting thai SFFSFL of serum amyloid A protein is important for the polypeptide self-assembly. These results further substantiate the ability of the present invention to predict amyloidogenic peptide sequences. EXAMPLE 24 identijlcalion of an amyloidogenic peptide from BriL The human BRJ gene is located on chromosome 13. The amyloid fibrils of the BriL gene product (GenBank Accession N'o. gi,T2643343) are associated with neuronal dysfunction and dementia (Vidal et at (1999) Nature 399, 776-78!). Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic features of a BriL-derived peptide, FENKF (SEQ ID NO: 34) were studied. Materials and Experimental Procedures -'Descnhed in Examples 7 and 10. Results - To characterize the ability of the BriL-derived peptide to form fibrilar supramolecular ultiastructures, negative staining'.plection microscopy analysis was effected. As shown in Figure 27, under mild conditions, filamentous structures were observed for the selected peptide, suggesting that FENKF of BriL is important for the polypeptide self-assembly. These results fijrther substantiate the ability of the present invention to predict amyloidogenic pepride sequences. £XAAfPLE25 Identification of an antyloidogenic peptide from Gelsolin Fragments of Gelsolin proteins (GenBank Accession No. gi:4504l65) were found in amyloid-state in cases of Finnish hereditary amyloidosis [Maury and Numiiaho-LassJla (S992) Biochem. Biophys. Res. Cormnun. 1S3: 227-31]. Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic features of a Gelsolin-derived peptide, SF\NG (SEQ ID NO: 35) were studied. Materials and Expurimeniai Procedures - Described in Examples 7 and 10. Results - To characterize the ability of the Gelsolin-derived peptide to form fibrilar supramoiecular ultrastructures. negative staining electron microscopy analysis was effected. .A.S shown in Figure CS, under mild conditions, filamenlous structures were observed for the selected peptide, suggesting that SFNNG of BriL is important for the po\>'pepude self-assembly. These results further substantiate the ability of the present invention to predict amyloidogenic peptide sequences. E.'^i.XfPlE 26 Identijication of an amyloidogenic peptide from Serum amyloid P Amyloid fibri! formation by beta-amyloid is promoted by inteyaction with serum amyloid-P {GenBank Accession No. gi:2144S84). Based on the proposed role of aromatic residues in amyJoid self-assembly, the amyloidogenic features of a Serum amyloid P-derived peptide, LQNFTL (SEQ ED NO: 36) were studied. Materials and Experimental Procedures - Described in Examples 7 and 10. Results - To characterize the abilit"/ of the Serum amyloid P-derived peptide to form fibrilar supramoiecular ultrastructures, negative staining electron microscopy analysis was effected. As shown in Figure 29, under mild conditions, filamentous structures were observed for the selected peptide, suggesting that LQNFTL of Serum amyloid P is important for the jjolypeptide self-assembly. These results further substantiate the ability of the present invention to predict amyloidogenic peptide jequences. EXAMPLE 27 Identijication of an amyloidogenic peptide from Immunoglobulin light chain Amyloid fibrils formation by Immunoglobulin light chain (GenBank Accession ■Jo. gi:625508) is associated with primary systemic amyloidosis [Sacchertini and I.elly (2002) Nat Rev Drug Discov 1:267-75]- Based on the proposed role of aromatic (Cbiuues m amyioici seii-assembiy, the amyloidogenic features of an Immunoglobulin light chain-derived peptide, TLrFGG (SEQ ID NO: 37) were studied. Materials and Experimenlal Procedures - Described in Examples 7 and 10. Results - To characterize the ability of the immunoglobulins light chain-derived peptide to form fibriJar siipramolecular ultrastructures, negative staining electron microscopy analysis was effecteii. As shown in Figure 30, under mild conditions, filamentous structures were observed for the selected peptide, suggesting that TLIFGG of the immunoglobulin light chain is important for the polypeptide self-assembly. Thes5 results further substantiate the ability of the present invention to predict amyioidogemc peptide sequences. EXAMPLE 28 Identification of an amyloidogenic peptide from Cystatin C Amyloid fibrii formation by Cystatin C (GenBank Accession No. gi:4490944) is associated with hereditary cerebral amyloid angiopathy [Sacchettini and Kelly (2002) Nat Rev Drug Discov 1:267-75]. Based on the proposed role of aromatic residues in amyloid self-assembly, the amvloidogenic features of a Cystatin C-derived peptide, RALDFA (SEQ ID NO; 38) were s;udied. Materials and Experimental Procedures -Dtscrihed in Examples 7 and 10. Results - To characterize the abiUt^y of the Cystatin C-derived peptide to form fibrilar supramolecular ultrastructures, negative staining electron microscopy analysis was effected. As shown in Figure 31, under mild conditions, filamentous structures were observed for the selected peptide, suggesting that RALDFA of the Cystatin C is important for the polypeptide self-assembly. These results further substantiate the ability of the present invention to predict amyloidogenic peptide sequences. EXAMPLE 29 Identification of an amyloidogenic peptide from Transthyretin Amyloid fibril formation by TransthvTCtin (GenBank Accession No. gi:72095) is associated with familial amyloid polyneuropathy (Sacchettini and Kelly (2002) Nat Rev Drug Discov 1:267-75). Based on the proposed role of aromatic residues in amyloid seif-assembly, the amyloidogenic features of an Transthyretin-derived peptide, GLVFVS (SEQ ID NO: 39) were studied. Materials and Experimental Procedures - Described in Examples 7 and 10. Resaits - To characterize the ability of the Translhyrelin-derived peptide to form fibrilar supramolecular uItrastrjcruxes, negative staining electron microscopy analysis was effected. As shown in Figure 32, under mild conditions, filamentous structures were observed for the selected peptide, suggesting that GL\TVS of Transthyretin is important for the poW-peplide self-assembly. These results farther substantiate the abiliry of the presenl invention to predict amyloidogenic peptide sequences. EXAMPLE 30 Identification of an amyloidogenic peptide from Lysozyme Amyloid fibril formation by Lysoz>'Tne (GenBank Accession No, gi:299033) is associated with familial non-neuropathic amyioidosis (Sacchettini and Kelly (2002) Nat Rev Drug Discov 1:267-75]. Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic features of a Lysozyme-derived peptide, GTFQIN (SEQ ID NO: 40) were studied. Materials and Experimental Procedures - Described in Examples 7 and ! 0. Results - To characterize the ability of the Lysozyme-derived peptide to form fibrilar supramolecular ultrastructures, negative staining electron microscopy analysis was effected. As shown in Figure 33, under mild conditions, filamentous structures were observed for the selected peptide, suggesting that GTFQIN of Lysozyme is important for the polypeptide self-assembly. These results iurther substantiate the ability of the present invention to predict amyloidogenic peptide sequences. EXAMPLE 31 Identification of an amyloidogenic peptide from Fibrinogen Amyloid fibnl formation by Fibrinogen (GenBank Accession No. gi: 11761629) s associated with hereditary renal amyloidosis (Sacchettini and Kelly (2002) Nat Rev !)rug Discov 1:267-75). Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic featwes of a Fibnnogen-derived peptide, SGIFTN (SEQ tD NO: 41) were studied. Materials and Experimenial Procedures - Described in Examples 7 and 10, Results - To charactenze the ability of the Fibrinogen -derived pepLide to form fibrilar supramolecular ultrsstruclurss, negative staining electron microscopy analysis was effected. As shown in Figure 34, under mild conditions, filanienious structures were observed for the selected peptide, suggesting that SGIFTN of Fibrinogen is important for the poK-peptide self-assembly. These results mrther substantiate the ability of the present invention to predict amyloidogenic peptide sequences. EXAMPLE 32 Identification of an amyloidogenic peptide from Insulin Amyloid fibnl formanon by Insulin (GenBank Accession No. gi;229!22) is associated with injection-localized amyloidosis [Sacchettini and Kelly (2002) Nat Rev Drug Discov 1:267-75]. Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic feamres of an insulin-derived peptide, ERGfF (SEQ ID NO: 42) were studied. Materials and Experimental Procedures — Described in Examples 7 and 10. Results ~ To characterize the ability of the Iiisulin-derived peptide to fonn fibrilar supramolecular ultrastructures, negative staining electron microscopy analysis was effected. As shown in Figure 35, under mild conditions, filamentous structures were observed for the selected peptide, suggesting that ERGFF of insuliri is important for the polypeptide self-assembly. These results further substantiate the ability of the present invention to predict amyloidogenic peptide sequences. EXAMPLE 33 Identification of an amyloidogenic peptide from prolactin Amyloid fibrils formation by prolactin (GenBank Accession No. gi;4506105) is associated with pituitary-gland amyloidosis (Sacchettini and Kelly (2002) Nat Rev Drug Discov 1:267-75). Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic features of a prolactin-derived peptide, RDFLDR (SEQ ID NO: 43) were studied. Materials and Experimental Procedures - Described in Examples 7 and 10. Results - To characterize the abiliry of the prolactin-derivcd peptide lo form fibrilar supramolecular ultrastTuctures. negative staining electron microscopy analysis was effected. As shov.'n in Figure 36. under mild conditions, filamentous strjcfures were obser\-ed for the selected peptide, suggesting that RDFLDR of prolactin is important for the pol)peptide seif-asserr.tly. These results further substantiate the ability of the present invention lo predict amyloidogenic peptide sequences. EXAMPLE 34 Identification of an amyloidogenic peptide from Beta-2'microglobulin Amyloid fibrils formation by beta-2-microtublin (GenBank Accession No. gi:70065) is associated haemodialysis-related amyloidosis (Sacchettini and Kelly (2002) Nat Rev Dr\ig D\scov !:267-75). Based on the proposed role of aromatic residues in amyloid self-assembly, the amyloidogenic features of a beta-2-microtublin -derived peptide, SNFLN (SEQ fD NO: 44) were studied. Materials and Experimental Procedures - Described in Examples 7 and ! 0. Results - To characterize the ability of the beta-2-microtublin-derived peptide to form fibrilar supramolecular ultrastructures, negative staining electron microscopy analysis was effected. As shown in Figure 37, under mild conditions, filamentous structures were observed for the selected peptide, suggesting that SNFLN of beta-2-microtublin is important for the polypeptide self-assembly. These results further substantiate the ability of the present invention to predict amyloidogenic peptide sequences. EXAMPLE 15 Inhibition of amyloid formation an amyloidogenic peptide identified according (o the teachings of the present invention The ability of amyloidogenic peptides of lAPP, identified according to the teachings of the present invention to inhibit amyloid formation by the full-length polypeptide was tested by the addition of beta-breaker proline residues to the recognition sequence as set forth in the peptide sequence NFLVHPP (SEQ D NO: 45). The degree of amyloid fibriis formation with and without Ihe inbibhor was assessed using thioflavin T (ThT) as molecular indicator. The degree of fluorescence of the ThT dye is directly correlated with the amount of amyloid fibrils in the solution [LcVine H 3rd- (1993) Protein Sci. 2;404-4!0, \AP? solutions (4 ^M hLAPPm 10 mM Tris buffer pH 7.2), were incubated in the presence or absence of 40 fiM of the modified peptide (i.e., NFLVHPP) ai room temperature. Fibril formation was deterfnined by a ten fold dilution of the solutions into a soiution that contained 3 jiM ihiollavin T (ThT) in 50 m.M sodium phosphate pH 6.0 and determination of fluorescence at 480 nm with excitation at 450 nm using a LS50B spectroflurimeter (PerJdn Elmar, Wellesiey, MA). As a control 10 mM Tris buffer pH 7.2 were diluted into the ThT solution and fluorescence was determined as described. Result - As shown in Figure 38, while the lAPP alone showed high levels of ThT fluorescence as expected for amyloidogenic protein, there was a significant increase in fluorescence in the presence of the inhibitory peptide. Thus, these results validate the NFLVH sequence as the amyloidogenic determinant in the LAPP polypeptide. EXAMPLE 36 Significance of hydrophobic residues in amyloid assembly The significance of an aromatic residue in the basic amyloidogenic unit of lAPP has been demonstrated in Examples 1-5. As described, substitution Of a phenylalanine to an alanine abolished the ability of an amyloidogenic fragment (NAGAIL, SEQ ID NO: 9) to form amyloid fibrils in viiro. Based on this observation, the remarkable occurrence of aromatic residues in other short amyloid related sequences (Examples 12-35), and the well-known role of 7t-stacking in processes of self-assembly in chemistry and biochemistry, it was suggested that stacking of aromatic residues may play a role in the process of amyloid fibrils fomiation [Gazit (2002) FASEB J. 16:77-83]. The study was fiirther extended to indicate whether the phenylalanine residue is critical due to aromaticitv therenf or rp.iher due to its hvdmnbnhic nature. The effect of phenylalanine substitution wiih hydrophobic residues on the self assembly of the basic amyloidogenic unit of lAPP (i.e., NFGAJL peptide) was addressed. The list of peptides used in the study and designation thereof is presented in Table 6, below. EX.4MPLE37 Characterization of the aggregation kinetics of hydrophobically modified hlAPP peptide fragments as monitored by turbidity measurements Experimental Procedures ~ Effected as described in Example 8. Results To get insist into the aggregation potential of the hydrophobically-modified lAPP-derived peptide analogues, turbidity assay was performed. Freshly made stock solutions of the wild-type peptide and the various pqstide mutants were made in DMSO. The peptides -were then diluted to a buffer solution and the turbidity was monitored by following the absorbance at 405 nm as a function of time. As shown in Figure 39, significant increase in turbidity was observed for the wild-type NFGAILSS octapeptide within minutes following dilution thereof into the aqueous solution. The shape of the aggregation cur.-e resembled that of a saturation curve, with a rapid increase in turbidity in the first hour, followed by a much slower increase in turbidity over the entire incubation time monitored. This probably reflects a rapid aggregation process, with the number of &ee building blocks as the rate limiting factor. In contrast, none of the analogue peptides revealed any sisjiificant aggregative behavior and the turbidity of all the hydrophobic analogues as well as the alanine-substituted analogues remained ver.- low for at least 24 hours (Figure 39). To determine whether the non-aggregative behavior of the hydrophobic analogues is a result of extremely slow kinetics, peptide analogue solutions were incubated for ! week in the same expeririiental conditions and endpoint turbidity values were delermined. As shc-v-n m Fig'jre 30, some low degree of turbidit>' was observed with the NIGAILSS, and lower extent for the NLGAiLSS, NAGAILSS, and NVGAJLSS peptides in decreasing order of turbidity. However, even for the NIGAILSS, the degree of turbidity was significantly lower as compared to the wild-type KFGAILSS protein (Figure 40). Moreover, there was no correlation between aggregation potential and hydrophobicity or p-sheet forming tendency, since the lower degree of aggregation was observed with the substitution to the highly hydrophobic and p-sheet former, valine. The slight decrease in the endpoint turbidity value of the NFGAILSS wiid-t^pe peptide, as compared to the values obtained after 24 hours incubation, could reflect the formation of very large aggregates that adhere to the cuvette surface. EXAMPLE 3SUltrastructural analysis of hydropbobically modified hJAPP peptide fragments Electron microscopy analysis was effected as described in Example 10. ■■ An ultrastructural visualization of any possible structures formed by the various analogous peptides was effected following five days of incubation. This structural analysis represents the most sensitive method since various aggregates were visualized individually. For that aim, the occunence and characteristics of the formed structures were studied by electron microscopy using negative staining, with the same of peptide solution which were incubated in the aggregation assay (Exaniple 32). As expected, well-ordered fibnls were observed with the wild-type peptide NFGAILSS peptide fragment (Figures 41a-b). Some amorphous aggregates could be also seen with the modified fragments (Figures 4Ic-f). However, those structures were significantly less abundant on the microscope grid. Larger aggregative structures were observed with the more hyckophobic substitutions as compared to the alanine analogues. Yet, unlike the ordered fibrillar structures that were seen with the NFGAILSS peptide, as mentioned abo\e, these aggregates were quite rare and did not have ordered structures (Figures 4ic-f). Those irregular and sporadic structures are consistent with some degree of non-specific aggregation as expected afier long incubation of rather hydrophobic molecules, EXAMPLE 39 Determination of the specific function of phenylalanine in the lAPP self assembly To determine the specific role of the phenylalanine residue in L\PP-self assembly, a membrane-based binding assay was preformed in order to systematically explore the molecutar determinants that facilitate the ability of the full-length hIAPP to recognize the "basic amyloidogenic unit". To this end, the ability of \fBP-L'\PP (see Example 6) to interact with an array of peptides in which the phenylalanine position was systematically altered (SEQ ID NOs. 91-110), was addressed. Materials and Experimental Procedures - see Examples 6-7. Results A peptide anray corresponding to the SNNXGAILSS motif (SEQ ID NO; 90), where X is any natural amino-acid but cysteine was constructed. As showa in Figure 42a, binding of MBP-IAPP was clearly observe*^ to peptides which contained the aromatic tryptophan and phenylalanine residues at the X position (Figure 42a). Interestingly, binding was also observed upon substitution of phenylalanine With basic amino acids such as arginine and lysine. In contrast, no binding was observed with any of the hydrophobic substitutions of the position, even after long exposure of the membrane (Figure 42b). The short exposure binding was assessed using densitometry (Figure 42c). It will be appreciated though, that the measured binding should be interpreted as semiquantitative since the coupling efficiency during synthesis and therefore the amount of peptide per spot may vary. In this case, however, the marked difference in binding between the various peptide variants was very clear. lasen logemer, ail inese obser\-ations substantiate the role of aromatic 'esidues in the acceleration of amyloid formation processes. Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and /arialions will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit md broad scope of the appended claims. All publications, patents, and patent vpplications mentioned in ihis specification are herein incorporated in their entirety >y reference into the specillcation, lo the same extent as if each individual )ub!ication, patent, or patent application was specifically and individually indicated o be incorporated herein by reference. In addition, citation or identification of any eference in this application shall not be construed as an admission that such eference is available as prior art to the present invention. WE CLAIM: 1. A peptide comprising less than 10 amino acid residues, the peptide including an amino acid sequence as set forth in SEQ ID NO: 7 and a proline, wherein the peptide is capable of self-aggregating under physiological conditions. 2. The peptide as claimed in claim 1, wherein said amino acid sequence includes a polar uncharged amino acid selected from the group consisting of serine, threonine, asparagine, glutamine and natural derivatives thereof. 3. The peptide as claimed in claim 1, wherein said amino acid sequence includes at least one positively charged amino acid and at least one negatively charged amino acid. 4. The peptide as claimed in claim 3, wherein said at least one positively charged amino acid is selected from the group consisting of lysine, arginine and natural and synthetic derivatives thereof 5. The peptide as claimed in claim 3, wherein said at least one negatively charged amino acid is selected from the group consisting of asparlic acid, glutamic acid and natural and synthetic derivatives thereof i 6. The peptide as claimed in claim 1, wherein said amino acid sequence is selected from the group consisting of SEQ ID NO: 4, 12-19 and 27-45. 7. The peptide as claimed in claim 1, comprising at least two serine residues at a C-terminus thereof 8. The peptide as claimed in claim 1, wherein the peptide is a linear or cyclic peptide. 9. A pharmaceutical composition for treating or preventing an amyloid-associated disease comprising as an active ingredient the peptide as claimed in any of preceding claims and a pharmaceutically acceptable carrier or diluent.

Documents:

1671-chenp-2004 abstract-duplicate.pdf

1671-chenp-2004 abstract.pdf

1671-chenp-2004 claims-duplicate.pdf

1671-chenp-2004 claims.pdf

1671-chenp-2004 correspondence-others.pdf

1671-chenp-2004 correspondence-po.pdf

1671-chenp-2004 description (complete)-duplicate.pdf

1671-chenp-2004 description (complete).pdf

1671-chenp-2004 drawings-duplicate.pdf

1671-chenp-2004 form-1.pdf

1671-chenp-2004 form-18.pdf

1671-chenp-2004 form-26.pdf

1671-chenp-2004 form-3.pdf

1671-chenp-2004 form-5.pdf

1671-chenp-2004 pct search report.pdf

1671-chenp-2004 pct.pdf

1671-chenp-2004 petition.pdf