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Vol. 4, No. 1, 2007
Issue release date: April 2007

Amyloid-β Aggregation

Finder V.H. · Glockshuber R.
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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of AD is the accumulation of plaques in the brain of AD patients. The plaques predominantly consist of aggregates of amyloid-β (Aβ), a peptide of 39–42 amino acids generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that Aβ aggregates are ordered oligomers and the cause rather than a product of AD. The analysis of the assembly pathway of Aβ in vitro and biochemical characterization of Aβ deposits isolated from AD brains indicate that Aβ oligomerization occurs via distinct intermediates, including oligomers of 3–50 Aβ monomers, annular oligomers, protofibrils, fibrils and plaques. Of these, the most toxic species appear to be small Aβ oligomers. This article reviews the current knowledge of the mechanism of Aβ assembly in vivo and in vitro, as well as the influence of inherited amino acid replacements in Aβ and experimental conditions on Aβ aggregation. Challenges regarding the reproducible handling of the Aβ peptide for in vitro assembly studies are discussed.

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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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  1. Alzheimer A: Über eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiatr Psychisch-Gerichtl Med 1907;64:146–148.
  2. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 1985;82:4245–4249.
  3. Ross CA, Poirier MA: Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 2005;6:891–898.
  4. Dobson CM: Protein folding and misfolding. Nature 2003;426:884–890.
  5. Goedert M, Spillantini MG: A century of Alzheimer’s disease. Science 2006;314:777–781.
  6. Glenner GG, Wong CW: Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984;122:1131–1135.
  7. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, et al: Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 1992;359:322–325.
  8. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B: The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987;325:733–736.
  9. Johnson GV, Bailey CD: The p38 MAP kinase signaling pathway in Alzheimer’s disease. Exp Neurol 2003;183:263–268.
  10. Sandbrink R, Masters CL, Beyreuther K: APP gene family: alternative splicing generates functionally related isoforms. Ann NY Acad Sci 1996;777:281–287.
  11. Selkoe DJ: Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 2004;6:1054–1061.
  12. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–356.
  13. Jarrett JT, Lansbury PT Jr: Seeding ‘one-dimensional crystallization’ of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 1993;73:1055–1058.
  14. German DC, Eisch AJ: Mouse models of Alzheimer’s disease: insight into treatment. Rev Neurosci 2004;15:353–369.
  15. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996;274:99–102.
  16. Wong PC, Cai H, Borchelt DR, Price DL: Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci 2002;5:633–639.
  17. Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L Jr, Eckman C, Golde TE, Younkin SG: An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 1994;264:1336–1340.
  18. Irie K, Murakami K, Masuda Y, Morimoto A, Ohigashi H, Ohashi R, Takegoshi K, Nagao M, Shimizu T, Shirasawa T: Structure of beta-amyloid fibrils and its relevance to their neurotoxicity: implications for the pathogenesis of Alzheimer’s disease. J Biosci Bioeng 2005;99:437–447.
  19. Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M: Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1998;1:355–358.
  20. Mann DM, Yates PO, Marcyniuk B, Ravindra CR: The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol Appl Neurobiol 1986;12:447–457.
  21. Ghetti B, Murrell J, Spillantini MG: Mutations in the Tau gene cause frontotemporal dementia. Brain Res Bull 1999;50:471–472.
  22. Spillantini MG, Bird TD, Ghetti B: Frontotemporal dementia and parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 1998;8:387–402.
  23. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000;403:98–103.
  24. Soto C: Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 2003;4:49–60.
  25. Roberson ED, Mucke L: 100 years and counting: prospects for defeating Alzheimer’s disease. Science 2006;314:781–784.
  26. Lorenzo A, Yankner BA: Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc Natl Acad Sci USA 1994;91:12243–12247.
  27. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M: Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002;416:507–511.
  28. Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ: Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 2002;277:32046–32053.
  29. Selkoe DJ: Alzheimer’s disease is a synaptic failure. Science 2002;298:789–791.
  30. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002;416:535–539.
  31. Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ, Selkoe DJ: Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans 2002;30:552–557.
  32. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, et al: Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 1997;3:67–72.
  33. Mehta ND, Refolo LM, Eckman C, Sanders S, Yager D, Perez-Tur J, Younkin S, Duff K, Hardy J, Hutton M: Increased Abeta42(43) from cell lines expressing presenilin 1 mutations. Ann Neurol 1998;43:256–258.
  34. Kuo YM, Emmerling MR, Vigo-Pelfrey C, Kasunic TC, Kirkpatrick JB, Murdoch GH, Ball MJ, Roher AE: Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem 1996;271:4077–4081.
  35. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL: Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 1999;46:860–866.
  36. Lansbury PT Jr: Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease. Proc Natl Acad Sci USA 1999;96:3342–3344.
  37. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ: Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 1996;3:16–32.
  38. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH: Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 2005;8:79–84.
  39. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006;440:352–357.
  40. Small DH, Mok SS, Bornstein JC: Alzheimer’s disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci 2001;2:595–598.
  41. Lee SJ, Liyanage U, Bickel PE, Xia W, Lansbury PT Jr, Kosik KS: A detergent-insoluble membrane compartment contains A beta in vivo. Nat Med 1998;4:730–734.
  42. Zhang Y, McLaughlin R, Goodyer C, LeBlanc A: Selective cytotoxicity of intracellular amyloid beta peptide1–42 through p53 and Bax in cultured primary human neurons. J Cell Biol 2002;156:519–529.
  43. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J: Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 1999;155:853–862.
  44. Walsh DM, Hartley DM, Condron MM, Selkoe DJ, Teplow DB: In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692→Gly) Alzheimer’s disease. Biochem J 2001;355:869–877.
  45. Clippingdale AB, Wade JD, Barrow CJ: The amyloid-beta peptide and its role in Alzheimer’s disease. J Pept Sci 2001;7:227–249.
  46. Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB: Amyloid beta-protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci USA 2003;100:330–335.
  47. Coles M, Bicknell W, Watson AA, Fairlie DP, Craik DJ: Solution structure of amyloid beta-peptide(1–40) in a water-micelle environment: is the membrane-spanning domain where we think it is? Biochemistry 1998;37:11064–11077.
  48. Crescenzi O, Tomaselli S, Guerrini R, Salvadori S, D’Ursi AM, Temussi PA, Picone D: Solution structure of the Alzheimer amyloid beta-peptide (1–42) in an apolar microenvironment: similarity with a virus fusion domain. Eur J Biochem 2002;269:5642–5648.
  49. Zhang S, Iwata K, Lachenmann MJ, Peng JW, Li S, Stimson ER, Lu Y, Felix AM, Maggio JE, Lee JP: The Alzheimer’s peptide a beta adopts a collapsed coil structure in water. J Struct Biol 2000;130:130–141.
  50. Barrow CJ, Zagorski MG: Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition. Science 1991;253:179–182.
  51. Lazo ND, Grant MA, Condron MC, Rigby AC, Teplow DB: On the nucleation of amyloid beta-protein monomer folding. Protein Sci 2005;14:1581–1596.
  52. Xu Y, Shen J, Luo X, Zhu W, Chen K, Ma J, Jiang H: Conformational transition of amyloid beta-peptide. Proc Natl Acad Sci USA 2005;102:5403–5407.
  53. Garzon-Rodriguez W, Sepulveda-Becerra M, Milton S, Glabe CG: Soluble amyloid Abeta-(1–40) exists as a stable dimer at low concentrations. J Biol Chem 1997;272:21037–21044.
  54. Hilbich C, Kisters-Woike B, Reed J, Masters CL, Beyreuther K: Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer’s disease beta A4 peptides. J Mol Biol 1992;228:460–473.
  55. Roher AE, Chaney MO, Kuo YM, Webster SD, Stine WB, Haverkamp LJ, Woods AS, Cotter RJ, Tuohy JM, Krafft GA, et al: Morphology and toxicity of Abeta-(1–42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer’s disease. J Biol Chem 1996;271:20631–20635.
  56. Podlisny MB, Ostaszewski BL, Squazzo SL, Koo EH, Rydell RE, Teplow DB, Selkoe DJ: Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture. J Biol Chem 1995;270:9564–9570.
  57. Walsh DM, Tseng BP, Rydel RE, Podlisny MB, Selkoe DJ: The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 2000;39:10831–10839.
  58. Bitan G, Tarus B, Vollers SS, Lashuel HA, Condron MM, Straub JE, Teplow DB: A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization. J Am Chem Soc 2003;125:15359–15365.
  59. Levine H 3rd: Soluble multimeric Alzheimer beta(1–40) pre-amyloid complexes in dilute solution. Neurobiol Aging 1995;16:755–764.
  60. Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, Bahr M, Schmidt M, Bitner RS, Harlan J, et al: Globular amyloid beta-peptide oligomer – a homogenous and stable neuropathological protein in Alzheimer’s disease. J Neurochem 2005;95:834–847.
  61. LeVine H 3rd: Alzheimer’s beta-peptide oligomer formation at physiologic concentrations. Anal Biochem 2004;335:81–90.
  62. Townsend M, Shankar GM, Mehta T, Walsh DM, Selkoe DJ: Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol 2006;572:477–492.
  63. Chromy BA, Nowak RJ, Lambert MP, Viola KL, Chang L, Velasco PT, Jones BW, Fernandez SJ, Lacor PN, Horowitz P, et al: Self-assembly of Abeta(1–42) into globular neurotoxins. Biochemistry 2003;42:12749–12760.
  64. Klein WL, Stine WB Jr, Teplow DB: Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer’s disease. Neurobiol Aging 2004;25:569–580.
  65. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, et al: Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 1998;95:6448–6453.
  66. Harper JD, Wong SS, Lieber CM, Lansbury PT Jr: Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer’s disease. Biochemistry 1999;38:8972–8980.
  67. Georganopoulou DG, Chang L, Nam JM, Thaxton CS, Mufson EJ, Klein WL, Mirkin CA: Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proc Natl Acad Sci USA 2005;102:2273–2276.
  68. Kagan BL, Hirakura Y, Azimov R, Azimova R, Lin MC: The channel hypothesis of Alzheimer’s disease: current status. Peptides 2002;23:1311–1315.
  69. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr: Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 2002;418:291.
  70. Quist A, Doudevski I, Lin H, Azimova R, Ng D, Frangione B, Kagan B, Ghiso J, Lal R: Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci USA 2005;102:10427–10432.
  71. Mattson MP, Chan SL: Neuronal and glial calcium signaling in Alzheimer’s disease. Cell Calcium 2003;34:385–397.
  72. Arimon M, Diez-Perez I, Kogan MJ, Durany N, Giralt E, Sanz F, Fernandez-Busquets X: Fine structure study of Abeta1–42 fibrillogenesis with atomic force microscopy. FASEB J 2005;19:1344–1346.
  73. Harper JD, Lansbury PT Jr: Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem 1997;66:385–407.
  74. Harper JD, Wong SS, Lieber CM, Lansbury PT: Observation of metastable Abeta amyloid protofibrils by atomic force microscopy. Chem Biol 1997;4:119–125.
  75. Kheterpal I, Lashuel HA, Hartley DM, Walz T, Lansbury PT Jr, Wetzel R: Abeta protofibrils possess a stable core structure resistant to hydrogen exchange. Biochemistry 2003;42:14092–14098.
  76. Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB: Amyloid beta-protein fibrillogenesis: detection of a protofibrillar intermediate. J Biol Chem 1997;272:22364–22372.
  77. Williams AD, Sega M, Chen M, Kheterpal I, Geva M, Berthelier V, Kaleta DT, Cook KD, Wetzel R: Structural properties of Abeta protofibrils stabilized by a small molecule. Proc Natl Acad Sci USA 2005;102:7115–7120.
  78. Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, Benedek GB, Selkoe DJ, Teplow DB: Amyloid beta-protein fibrillogenesis: structure and biological activity of protofibrillar intermediates. J Biol Chem 1999;274:25945–25952.
  79. Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ: Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 1999;19:8876–8884.
  80. Rochet JC, Lansbury PT Jr: Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol 2000;10:60–68.
  81. Klunk WE, Jacob RF, Mason RP: Quantifying amyloid by Congo red spectral shift assay. Methods Enzymol 1999;309:285–305.
  82. LeVine H 3rd: Quantification of beta-sheet amyloid fibril structures with thioflavin T. Methods Enzymol 1999;309:274–284.
  83. Kirschner DA, Inouye H, Duffy LK, Sinclair A, Lind M, Selkoe DJ: Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro. Proc Natl Acad Sci USA 1987;84:6953–6957.
  84. Stromer T, Serpell LC: Structure and morphology of the Alzheimer’s amyloid fibril. Microsc Res Tech 2005;67:210–217.
  85. Kheterpal I, Williams A, Murphy C, Bledsoe B, Wetzel R: Structural features of the Abeta amyloid fibril elucidated by limited proteolysis. Biochemistry 2001;40:11757–11767.
  86. Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, Tycko R: A structural model for Alzheimer’s beta-amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci USA 2002;99:16742–16747.
  87. Guo JT, Wetzel R, Xu Y: Molecular modeling of the core of Abeta amyloid fibrils. Proteins 2004;57:357–364.
  88. Egnaczyk GF, Greis KD, Stimson ER, Maggio JE: Photoaffinity cross-linking of Alzheimer’s disease amyloid fibrils reveals interstrand contact regions between assembled beta-amyloid peptide subunits. Biochemistry 2001;40:11706–11714.
  89. Balbach JJ, Petkova AT, Oyler NA, Antzutkin ON, Gordon DJ, Meredith SC, Tycko R: Supramolecular structure in full-length Alzheimer’s beta-amyloid fibrils: evidence for a parallel beta-sheet organization from solid-state nuclear magnetic resonance. Biophys J 2002;83:1205–1216.
  90. Antzutkin ON, Leapman RD, Balbach JJ, Tycko R: Supramolecular structural constraints on Alzheimer’s beta-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry 2002;41:15436–15450.
  91. Hou L, Zagorski MG: Sorting out the driving forces for parallel and antiparallel alignment in the abeta peptide fibril structure. Biophys J 2004;86:428–434.
  92. Luhrs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Dobeli H, Schubert D, Riek R: 3D structure of Alzheimer’s amyloid-beta(1–42) fibrils. Proc Natl Acad Sci USA 2005;102:17342–17347.
  93. Sachse C, Xu C, Wieligmann K, Diekmann S, Grigorieff N, Fandrich M: Quaternary structure of a mature amyloid fibril from Alzheimer’s Abeta(1–40) peptide. J Mol Biol 2006;362:347–354.
  94. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R: Self-propagating, molecular-level polymorphism in Alzheimer’s beta-amyloid fibrils. Science 2005;307:262–265.
  95. Weissmann C: The state of the prion. Nat Rev Microbiol 2004;2:861–871.
  96. Muller-Hill B, Beyreuther K: Molecular biology of Alzheimer’s disease. Annu Rev Biochem 1989;58:287–307.
  97. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R: Physical basis of cognitive alterations inAlzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572–580.
  98. Teplow DB: Structural and kinetic features of amyloid beta-protein fibrillogenesis. Amyloid 1998;5:121–142.
  99. Carrotta R, Manno M, Bulone D, Martorana V, San Biagio PL: Protofibril formation of amyloid beta-protein at low pH via a non-cooperative elongation mechanism. J Biol Chem 2005;280:30001–30008.
  100. Mastrangelo IA, Ahmed M, Sato T, Liu W, Wang C, Hough P, Smith SO: High-resolution atomic force microscopy of soluble Abeta42 oligomers. J Mol Biol 2006;358:106–119.
  101. Piccini A, Russo C, Gliozzi A, Relini A, Vitali A, Borghi R, Giliberto L, Armirotti A, D’Arrigo C, Bachi A, et al: Beta-amyloid is different in normal aging and in Alzheimer disease. J Biol Chem 2005;280:34186–34192.
  102. Caughey B, Lansbury PT: Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 2003;26:267–298.
  103. Lomakin A, Chung DS, Benedek GB, Kirschner DA, Teplow DB: On the nucleation and growth of amyloid beta-protein fibrils: detection of nuclei and quantitation of rate constants. Proc Natl Acad Sci USA 1996;93:1125–1129.
  104. O’Nuallain B, Williams AD, Westermark P, Wetzel R: Seeding specificity in amyloid growth induced by heterologous fibrils. J Biol Chem 2004;279:17490–17499.
  105. Sengupta P, Garai K, Sahoo B, Shi Y, Callaway DJ, Maiti S: The amyloid beta peptide (Abeta(1–40)) is thermodynamically soluble at physiological concentrations. Biochemistry 2003;42:10506–10513.
  106. Fraser PE, Nguyen JT, Inouye H, Surewicz WK, Selkoe DJ, Podlisny MB, Kirschner DA: Fibril formation by primate, rodent, and Dutch-hemorrhagic analogues of Alzheimer amyloid beta-protein. Biochemistry 1992;31:10716–10723.
  107. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW: Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 1993;13:1676–1687.
  108. Huang TH, Yang DS, Plaskos NP, Go S, Yip CM, Fraser PE, Chakrabartty A: Structural studies of soluble oligomers of the Alzheimer beta-amyloid peptide. J Mol Biol 2000;297:73–87.
  109. Lomakin A, Teplow DB, Kirschner DA, Benedek GB: Kinetic theory of fibrillogenesis of amyloid beta-protein. Proc Natl Acad Sci USA 1997;94:7942–7947.
  110. O’Nuallain B, Shivaprasad S, Kheterpal I, Wetzel R: Thermodynamics of A beta(1–40) amyloid fibril elongation. Biochemistry 2005;44:12709–12718.
  111. Pallitto MM, Murphy RM: A mathematical model of the kinetics of beta-amyloid fibril growth from the denatured state. Biophys J 2001;81:1805–1822.
  112. Soto C, Castano EM, Kumar RA, Beavis RC, Frangione B: Fibrillogenesis of synthetic amyloid-beta peptides is dependent on their initial secondary structure. Neurosci Lett 1995;200:105–108.
  113. Wood SJ, Wetzel R, Martin JD, Hurle MR: Prolines and amyloidogenicity in fragments of the Alzheimer’s peptide beta/A4. Biochemistry 1995;34:724–730.
  114. Kirkitadze MD, Condron MM, Teplow DB: Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. J Mol Biol 2001;312:1103–1119.
  115. Li L, Darden TA, Bartolotti L, Kominos D, Pedersen LG: An atomic model for the pleated beta-sheet structure of Abeta amyloid protofilaments. Biophys J 1999;76:2871–2878.
  116. Ban T, Hoshino M, Takahashi S, Hamada D, Hasegawa K, Naiki H, Goto Y: Direct observation of Abeta amyloid fibril growth and inhibition. J Mol Biol 2004;344:757–767.
  117. Carulla N, Caddy GL, Hall DR, Zurdo J, Gairi M, Feliz M, Giralt E, Robinson CV, Dobson CM: Molecular recycling within amyloid fibrils. Nature 2005;436:554–558.
  118. Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee VM, Doms RW: Alzheimer’s A beta(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med 1997;3:1021–1023.
  119. Haass C, Hung AY, Schlossmacher MG, Oltersdorf T, Teplow DB, Selkoe DJ: Normal cellular processing of the beta-amyloid precursor protein results in the secretion of the amyloid beta peptide and related molecules. Ann NY Acad Sci 1993;695:109–116.
  120. Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ: Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 1992;357:500–503.
  121. Hartmann T, Bieger SC, Bruhl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K: Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nat Med 1997;3:1016–1020.
  122. Koo EH, Squazzo SL, Selkoe DJ, Koo CH: Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody. J Cell Sci 1996;109:991–998.
  123. Soriano S, Chyung AS, Chen X, Stokin GB, Lee VM, Koo EH: Expression of beta-amyloid precursor protein-CD3gamma chimeras to demonstrate the selective generation of amyloid beta(1–40) and amyloid beta(1–42) peptides within secretory and endocytic compartments. J Biol Chem 1999;274:32295–32300.
  124. Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ: Experimental induction of beta-amyloid plaques and cerebral angiopathy in primates. Ann NY Acad Sci 1993;695:228–231.
  125. Buckig A, Tikkanen R, Herzog V, Schmitz A: Cytosolic and nuclear aggregation of the amyloid beta-peptide following its expression in the endoplasmic reticulum. Histochem Cell Biol 2002;118:353–360.
  126. Skovronsky DM, Doms RW, Lee VM: Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture. J Cell Biol 1998;141:1031–1039.
  127. Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, et al: Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 2000;156:15–20.
  128. Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, Bird TD, Schellenberg GD: A familial Alzheimer’s disease locus on chromosome 1. Science 1995;269:970–973.
  129. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, et al: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754–760.
  130. Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frebourg T, Checler F: Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 → Met betaAPP-770 mutation responsible for probable early-onset Alzheimer’s disease. Proc Natl Acad Sci USA 1999;96:4119–4124.
  131. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ: Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 1992;360:672–674.
  132. Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L: A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1992;1:345–347.
  133. Pangalos MN, Jacobsen SJ, Reinhart PH: Disease modifying strategies for the treatment of Alzheimer’s disease targeted at modulating levels of the beta-amyloid peptide. Biochem Soc Trans 2005;33:553–558.
  134. Hardy J: Amyloid double trouble. Nat Genet 2006;38:11–12.
  135. Mayeux R, Tang MX, Jacobs DM, Manly J, Bell K, Merchant C, Small SA, Stern Y, Wisniewski HM, Mehta PD: Plasma amyloid beta-peptide 1–42 and incipient Alzheimer’s disease. Ann Neurol 1999;46:412–416.
  136. Clements A, Walsh DM, Williams CH, Allsop D: Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer’s amyloid beta/A4 peptide. Neurosci Lett 1993;161:17–20.
  137. Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J: Substitutions at codon 22 of Alzheimer’s abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem 2000;275:27110–27116.
  138. Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, et al: The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci 2001;4:887–893.
  139. Van Nostrand WE, Melchor JP, Cho HS, Greenberg SM, Rebeck GW: Pathogenic effects of D23N Iowa mutant amyloid beta-protein. J Biol Chem 2001;276:32860–32866.
  140. Kumar-Singh S, Julliams A, Nuydens R, Ceuterick C, Labeur C, Serneels S, Vennekens K, Van Osta P, Geerts H, De Strooper B, Van Broeckhoven C: In vitro studies of Flemish, Dutch, and wild-type beta-amyloid provide evidence for two-staged neurotoxicity. Neurobiol Dis 2002;11:330–340.
  141. Lashuel HA, Hartley DM, Petre BM, Wall JS, Simon MN, Walz T, Lansbury PT Jr: Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores. J Mol Biol 2003;332:795–808.
  142. Fung J, Frost D, Chakrabartty A, McLaurin J: Interaction of human and mouse Abeta peptides. J Neurochem 2004;91:1398–1403.
  143. Kim W, Hecht MH: Sequence determinants of enhanced amyloidogenicity of Alzheimer A{beta}42 peptide relative to A{beta}40. J Biol Chem 2005;280:35069–35076.
  144. Barnham KJ, Masters CL, Bush AI: Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 2004;3:205–214.
  145. Bush AI: The metallobiology of Alzheimer’s disease. Trends Neurosci 2003;26:207–214.
  146. Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN: Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev 2003;43:1–16.
  147. Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H, Leiter L, McPhee J, Sarang SS, Utsuki T, et al: An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 2002;277:45518–45528.
  148. Curtain CC, Ali FE, Smith DG, Bush AI, Masters CL, Barnham KJ: Metal ions, pH, and cholesterol regulate the interactions of Alzheimer’s disease amyloid-beta peptide with membrane lipid. J Biol Chem 2003;278:2977–2982.
  149. Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX: Metals and amyloid-beta in Alzheimer’s disease. Int J Exp Pathol 2005;86:147–159.
  150. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR: Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 1998;158:47–52.
  151. Huang X, Atwood CS, Moir RD, Hartshorn MA, Vonsattel JP, Tanzi RE, Bush AI: Zinc-induced Alzheimer’s Abeta1–40 aggregation is mediated by conformational factors. J Biol Chem 1997;272:26464–26470.
  152. Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, Bush AI: Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 1998;273:12817–12826.
  153. Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY: Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci USA 2002;99:7705–7710.
  154. Cuajungco MP, Faget KY, Huang X, Tanzi RE, Bush AI: Metal chelation as a potential therapy for Alzheimer’s disease. Ann NY Acad Sci 2000;920:292–304.
  155. Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, et al: The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 1999;38:7609–7616.
  156. Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, Cappai R, Masters CL, Tanzi RE, Inestrosa NC, Bush AI: Metalloenzyme-like activity of Alzheimer’s disease beta-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem 2002;277:40302–40308.
  157. Butterfield DA, Boyd-Kimball D: The critical role of methionine 35 in Alzheimer’s amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity. Biochim Biophys Acta 2005;1703:149–156.
  158. Schoneich C: Methionine oxidation by reactive oxygen species: reaction mechanisms and relevance to Alzheimer’s disease. Biochim Biophys Acta 2005;1703:111–119.

    External Resources

  159. Hou L, Kang I, Marchant RE, Zagorski MG: Methionine 35 oxidation reduces fibril assembly of the amyloid abeta-(1–42) peptide of Alzheimer’s disease. J Biol Chem 2002;277:40173–40176.
  160. Palmblad M, Westlind-Danielsson A, Bergquist J: Oxidation of methionine 35 attenuates formation of amyloid beta-peptide 1–40 oligomers. J Biol Chem 2002;277:19506–19510.
  161. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921–923.
  162. LaDu MJ, Falduto MT, Manelli AM, Reardon CA, Getz GS, Frail DE: Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 1994;269:23403– 23406.
  163. Naslund J, Thyberg J, Tjernberg LO, Wernstedt C, Karlstrom AR, Bogdanovic N, Gandy SE, Lannfelt L, Terenius L, Nordstedt C: Characterization of stable complexes involving apolipoprotein E and the amyloid beta peptide in Alzheimer’s disease brain. Neuron 1995;15:219–228.
  164. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, et al: A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000;408:982–985.
  165. Lendon C, Craddock N: Susceptibility gene(s) for Alzheimer’s disease on chromosome 10. Trends Neurosci 2001;24:557–559.
  166. Shen CL, Murphy RM: Solvent effects on self-assembly of beta-amyloid peptide. Biophys J 1995;69:640–651.
  167. Yamamoto N, Igbabvoa U, Shimada Y, Ohno-Iwashita Y, Kobayashi M, Wood WG, Fujita SC, Yanagisawa K: Accelerated Abeta aggregation in the presence of GM1-ganglioside-accumulated synaptosomes of aged apoE4-knock-in mouse brain. FEBS Lett 2004;569:135–139.
  168. Hilbich C, Kisters-Woike B, Reed J, Masters CL, Beyreuther K: Aggregation and secondary structure of synthetic amyloid beta A4 peptides of Alzheimer’s disease. J Mol Biol 1991;218:149–163.
  169. Barrow CJ, Yasuda A, Kenny PT, Zagorski MG: Solution conformations and aggregational properties of synthetic amyloid beta-peptides of Alzheimer’s disease: analysis of circular dichroism spectra. J Mol Biol 1992;225:1075–1093.
  170. Burdick D, Soreghan B, Kwon M, Kosmoski J, Knauer M, Henschen A, Yates J, Cotman C, Glabe C: Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. J Biol Chem 1992;267:546–554.
  171. Fraser PE, Nguyen JT, Surewicz WK, Kirschner DA: pH-dependent structural transitions of Alzheimer amyloid peptides. Biophys J 1991;60:1190–1201.
  172. Wood SJ, Maleeff B, Hart T, Wetzel R: Physical, morphological and functional differences between pH 5.8 and 7.4 aggregates of the Alzheimer’s amyloid peptide Abeta. J Mol Biol 1996;256:870–877.
  173. Howlett DR, Jennings KH, Lee DC, Clark MS, Brown F, Wetzel R, Wood SJ, Camilleri P, Roberts GW: Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide. Neurodegeneration 1995;4:23–32.
  174. Danielsson J, Jarvet J, Damberg P, Graslund A: The Alzheimer beta-peptide shows temperature-dependent transitions between left-handed 3-helix, beta-strand and random coil secondary structures. FEBS J 2005;272:3938–3949.
  175. Kusumoto Y, Lomakin A, Teplow DB, Benedek GB: Temperature dependence of amyloid beta-protein fibrillization. Proc Natl Acad Sci USA 1998;95:12277–12282.
  176. Zagorski MG, Yang J, Shao H, Ma K, Zeng H, Hong A: Methodological and chemical factors affecting amyloid beta peptide amyloidogenicity. Methods Enzymol 1999;309:189–204.
  177. Davis J, Van Nostrand WE: Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein. Proc Natl Acad Sci USA 1996;93:2996–3000.
  178. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y: Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 1994;13:45–53.
  179. Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, Ball MJ: beta-Amyloid-(1–42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci USA 1993;90:10836–10840.
  180. Shapira R, Austin GE, Mirra SS: Neuritic plaque amyloid in Alzheimer’s disease is highly racemized. J Neurochem 1988;50:69–74.
  181. Tomiyama T, Asano S, Furiya Y, Shirasawa T, Endo N, Mori H: Racemization of Asp23 residue affects the aggregation properties of Alzheimer amyloid beta protein analogues. J Biol Chem 1994;269:10205–10208.
  182. Kuo YM, Webster S, Emmerling MR, De Lima N, Roher AE: Irreversible dimerization/tetramerization and post-translational modifications inhibit proteolytic degradation of A beta peptides of Alzheimer’s disease. Biochim Biophys Acta 1998;1406:291–298.
  183. Szendrei GI, Prammer KV, Vasko M, Lee VM, Otvos L Jr: The effects of aspartic acid-bond isomerization on in vitro properties of the amyloid beta-peptide as modeled with N-terminal decapeptide fragments. Int J Pept Protein Res 1996;47:289–296.
  184. Ohm TG, Muller H, Braak H, Bohl J: Close-meshed prevalence rates of different stages as a tool to uncover the rate of Alzheimer’s disease-related neurofibrillary changes. Neuroscience 1995;64:209–217.
  185. Solomon B: Alzheimer’s disease immunotherapy: from in vitro amyloid immunomodulation to in vivo vaccination. J Alzheimers Dis 2006;9:433–438.
  186. Solomon B: Towards Alzheimer’s disease vaccination. Mini Rev Med Chem 2002;2:85–92.
  187. Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM: Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med 2002;8:1270–1275.
  188. Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, et al: Antibodies against beta-amyloid slow cognitive decline in Alzheimer’s disease. Neuron 2003;38:547–554.
  189. Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA: Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer’s disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci 2006;26:4717–4728.
  190. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, et al: Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995;373:523–527.
  191. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, et al: Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001;293:1487–1491.
  192. Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG: A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 2000;408:975–979.
  193. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, et al: Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997;94:13287–13292.
  194. Van Dam D, De Deyn PP: Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 2006;5:956–970.
  195. Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA: Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med 1998;4:827–831.
  196. Koistinaho M, Ort M, Cimadevilla JM, Vondrous R, Cordell B, Koistinaho J, Bures J, Higgins LS: Specific spatial learning deficits become severe with age in beta-amyloid precursor protein transgenic mice that harbor diffuse beta-amyloid deposits but do not form plaques. Proc Natl Acad Sci USA 2001;98:14675–14680.
  197. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L: High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000;20:4050–4058.
  198. Dobeli H, Draeger N, Huber G, Jakob P, Schmidt D, Seilheimer B, Stuber D, Wipf B, Zulauf M: A biotechnological method provides access to aggregation competent monomeric Alzheimer’s 1–42 residue amyloid peptide. Biotechnology (NY) 1995;13:988–993.
  199. Nakabayashi J, Yoshimura M, Morishima-Kawashima M, Funato H, Miyakawa T, Yamazaki T, Ihara Y: Amyloid beta-protein (A beta) accumulation in the putamen and mammillary body during aging and in Alzheimer disease. J Neuropathol Exp Neurol 1998;57:343–352.
  200. Le Y, Gong W, Tiffany HL, Tumanov A, Nedospasov S, Shen W, Dunlop NM, Gao JL, Murphy PM, Oppenheim JJ, Wang JM: Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J Neurosci 2001;21:RC123.
  201. Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL: Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA 2003;100:10417–10422.
  202. Ward RV, Jennings KH, Jepras R, Neville W, Owen DE, Hawkins J, Christie G, Davis JB, George A, Karran EH, Howlett DR: Fractionation and characterization of oligomeric, protofibrillar and fibrillar forms of beta-amyloid peptide. Biochem J 2000;348:137–144.
  203. Malinchik SB, Inouye H, Szumowski KE, Kirschner DA: Structural analysis of Alzheimer’s beta(1–40) amyloid: protofilament assembly of tubular fibrils. Biophys J 1998;74:537–545.

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