Are β-sheet breaker peptides dissolving the therapeutic problem of Alzheimer’s disease?

  • B. Permanne
  • C. Adessi
  • S. Fraga
  • M.-J. Frossard
  • G. P. Saborio
  • C. Soto
Part of the Journal of Neural Transmission. Supplementa book series (NEURAL SUPPL, volume 62)


Alzheimer’s disease (AD) is a neurodegenerative disorder for which there is no cure or effective treatment. One of the major neuropatho-logical signatures of AD is the deposition of amyloid plaques in the brain of affected people. Although the role of these structures in the pathogenesis of the disease is not fully understood, recent findings have provided evidence that amyloid may be a key player in the disease. Therefore, preventing and reversing cerebral amyloid deposition have become an attractive therapeutic strategy for AD. We have engineered synthetic β-sheet breaker peptides to bind soluble amyloid peptide and prevent and reverse its conversion to the β-sheet rich aggregated structure, precursor of the amyloid plaques. Results in vitro, in cell culture and in vivo suggest that β-sheet breaker peptides might be candidates for an AD-therapy focused to reduce amyloid deposition.


Down Syndrome Amyloid Precursor Protein Amyloid Plaque Amyloid Formation Attractive Therapeutic Strategy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Annaert W, Cupers P, Saftig P, De Strooper B (2000) Presenilin function in APP processing. Ann NY Acad Sci 920:158–164PubMedCrossRefGoogle Scholar
  2. Citron M (2000) Secretases as targets for the treatment of Alzheimer’s disease. Mol Med Today 6: 392–397PubMedCrossRefGoogle Scholar
  3. Duff K (1999) Curing amyloidosis: will it work in humans? Trends Neurosci 22: 485–486PubMedCrossRefGoogle Scholar
  4. Emilien G, Beyreuther K, Masters CL, Maloteaux JM (2000) Prospects for pharmacological intervention in Alzheimer disease. Arch Neurol 57: 454–459PubMedCrossRefGoogle Scholar
  5. Fortini ME (2001) Notch and presenilin: a proteolytic mechanism emerges. Curr Opin Cell Biol 13: 627–634PubMedCrossRefGoogle Scholar
  6. Fraser PE, Yang DS, Yu G, Levesque L, Nishimura M, Arawaka S, Serpell LC, Rogaeva E, George-Hyslop P (2000) Presenilin structure, function and role in Alzheimer disease. Biochim Biophys Acta 1502: 1–15PubMedCrossRefGoogle Scholar
  7. Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M (1998) Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1: 355–358PubMedCrossRefGoogle Scholar
  8. Hyman BT, Smith C, Buldyrev I, Whelan C, Brown H, Tang MX, Mayeux R (2001) Autoantibodies to amyloid-beta and Alzheimer’s disease. Ann Neurol 49: 808–810PubMedCrossRefGoogle Scholar
  9. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Home P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, George-Hyslop P, Westaway D (2000) A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408: 979–982PubMedCrossRefGoogle Scholar
  10. Kelly JW (1996) Alternative conformations of amyloidogenic proteins govern their behavior. Curr Opin Struct Biol 6: 11–17PubMedCrossRefGoogle Scholar
  11. Knopman D, Morris JC (1998) An update on primary drug therapies for Alzheimer’s disease. Arch Neurol 54:1406–1409CrossRefGoogle Scholar
  12. Lee VMY (2001) Aβimmunization: moving A(3 peptide from brain to blood. Proc Natl Acad Sci USA 98: 8931–8932PubMedCrossRefGoogle Scholar
  13. Mann DM (1989) Cerebral amyloidosis, ageing and Alzheimer’s disease; a contribution from studies on Down’s syndrome. Neurobiol Aging 10: 397–399PubMedCrossRefGoogle Scholar
  14. McKeon-O’Malley C, Saunders AJ, Bush AI, Tanzi RE (1998) Potential therapeutic targets for Alzheimer’s disease. Emerging Therapeutic Targets 2: 157–179CrossRefGoogle Scholar
  15. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408: 982–985PubMedCrossRefGoogle Scholar
  16. Price DL, Tanzi RE, Borchelt DR, Sisodia SS (1998) Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 32: 461–493PubMedCrossRefGoogle Scholar
  17. Sabbagh MN, Galasko D, Thai LJ (1997) (3-amyloid and treatment opportunities for Alzheimer’s disease. Alzheimer’s Disease Review 3: 1–19Google Scholar
  18. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400: 173–177PubMedCrossRefGoogle Scholar
  19. Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6: 487–498PubMedCrossRefGoogle Scholar
  20. Selkoe DJ (2000) Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann NY Acad Sci 924: 17–25PubMedCrossRefGoogle Scholar
  21. Selkoe DJ, Wolfe MS (2000) In search of gamma-secretase: presenilin at the cutting edge. Proc Natl Acad Sci USA 97: 5690–5692PubMedCrossRefGoogle Scholar
  22. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert R, Selkoe DJ, Lieberburg I, Schenk DB (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359: 325–327PubMedCrossRefGoogle Scholar
  23. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B, Younkin SG (1992) Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258: 126–129PubMedCrossRefGoogle Scholar
  24. Sigurdsson EM, Permanne B, Soto C, Wisniewski T, Frangione B (2000) In vivo reversal of amyloid-P lesions in rat brain. J Neuropathol Exp Neurol 59: 11–17PubMedGoogle Scholar
  25. Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T (2001) Immunization with a nontoxic/nonfibrillar amyloid-P homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am J Pathol 159: 439–447PubMedCrossRefGoogle Scholar
  26. Soto C (1999a) Plaque busters: strategies to inhibit amyloid formation in Alzheimer’s disease. Mol Med Today 5: 343–350CrossRefGoogle Scholar
  27. Soto C (1999b) P-amyloid disrupting drugs: potential in the treatment of Alzheimer’s disease. CNS Drugs 12: 347–356CrossRefGoogle Scholar
  28. Soto C (2001) Protein misfolding and disease; protein refolding and therapy. FEBS Lett 498: 204–207PubMedCrossRefGoogle Scholar
  29. Soto C, Branes MC, Alvarez J, Inestrosa NC (1994) Structural determinants of the Alzheimer’s amyloid beta-peptide. J Neurochem 63: 1191–1198PubMedCrossRefGoogle Scholar
  30. Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castano EM, Frangione B (1998) β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer’s therapy. Nature Med 4: 822–826PubMedCrossRefGoogle Scholar
  31. StGeorge-Hyslop PH, Westaway D (1999) Antibody clears senile plaques. Nature 400: 116–117CrossRefGoogle Scholar
  32. Teplow DB (1998) Structural and kinetic features of amyloid beta-protein fibrillogenesis. Amyloid 5:121–142PubMedCrossRefGoogle Scholar
  33. Terry RD (1994) Neuropathological changes in Alzheimer disease. Prog Brain Res 101: 383–390PubMedCrossRefGoogle Scholar
  34. Van Leuven F (2000) Single and multiple transgenic mice as models for Alzheimer’s disease. Prog Neurobiol 61: 305–312PubMedCrossRefGoogle Scholar
  35. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286: 735–741PubMedCrossRefGoogle Scholar
  36. Wolfe MS (2001a) Presenilin and gamma-secretase: structure meets function. J Neurochem 76:1615–1620CrossRefGoogle Scholar
  37. Wolfe MS (2001b) Secretase targets for Alzheimer’s disease: identification and therapeutic potential. J Med Chem 44: 2039–2060CrossRefGoogle Scholar
  38. Younkin SG (1995) Evidence that A(3 42 is the real culprit in Alzheimer’s disease. Ann Neurol 37: 287–288PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2002

Authors and Affiliations

  • B. Permanne
    • 1
  • C. Adessi
    • 1
  • S. Fraga
    • 1
  • M.-J. Frossard
    • 1
  • G. P. Saborio
    • 1
  • C. Soto
    • 1
  1. 1.Serono Pharmaceutical Research InstituteGenevaSwitzerland

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