Abstract
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.
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References
Annaert W, Cupers P, Saftig P, De Strooper B (2000) Presenilin function in APP processing. Ann NY Acad Sci 920:158–164
Citron M (2000) Secretases as targets for the treatment of Alzheimer’s disease. Mol Med Today 6: 392–397
Duff K (1999) Curing amyloidosis: will it work in humans? Trends Neurosci 22: 485–486
Emilien G, Beyreuther K, Masters CL, Maloteaux JM (2000) Prospects for pharmacological intervention in Alzheimer disease. Arch Neurol 57: 454–459
Fortini ME (2001) Notch and presenilin: a proteolytic mechanism emerges. Curr Opin Cell Biol 13: 627–634
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: 1–15
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: 355–358
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: 808–810
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: 979–982
Kelly JW (1996) Alternative conformations of amyloidogenic proteins govern their behavior. Curr Opin Struct Biol 6: 11–17
Knopman D, Morris JC (1998) An update on primary drug therapies for Alzheimer’s disease. Arch Neurol 54:1406–1409
Lee VMY (2001) Aβimmunization: moving A(3 peptide from brain to blood. Proc Natl Acad Sci USA 98: 8931–8932
Mann DM (1989) Cerebral amyloidosis, ageing and Alzheimer’s disease; a contribution from studies on Down’s syndrome. Neurobiol Aging 10: 397–399
McKeon-O’Malley C, Saunders AJ, Bush AI, Tanzi RE (1998) Potential therapeutic targets for Alzheimer’s disease. Emerging Therapeutic Targets 2: 157–179
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: 982–985
Price DL, Tanzi RE, Borchelt DR, Sisodia SS (1998) Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 32: 461–493
Sabbagh MN, Galasko D, Thai LJ (1997) (3-amyloid and treatment opportunities for Alzheimer’s disease. Alzheimer’s Disease Review 3: 1–19
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: 173–177
Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6: 487–498
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: 17–25
Selkoe DJ, Wolfe MS (2000) In search of gamma-secretase: presenilin at the cutting edge. Proc Natl Acad Sci USA 97: 5690–5692
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: 325–327
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: 126–129
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: 11–17
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: 439–447
Soto C (1999a) Plaque busters: strategies to inhibit amyloid formation in Alzheimer’s disease. Mol Med Today 5: 343–350
Soto C (1999b) P-amyloid disrupting drugs: potential in the treatment of Alzheimer’s disease. CNS Drugs 12: 347–356
Soto C (2001) Protein misfolding and disease; protein refolding and therapy. FEBS Lett 498: 204–207
Soto C, Branes MC, Alvarez J, Inestrosa NC (1994) Structural determinants of the Alzheimer’s amyloid beta-peptide. J Neurochem 63: 1191–1198
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: 822–826
StGeorge-Hyslop PH, Westaway D (1999) Antibody clears senile plaques. Nature 400: 116–117
Teplow DB (1998) Structural and kinetic features of amyloid beta-protein fibrillogenesis. Amyloid 5:121–142
Terry RD (1994) Neuropathological changes in Alzheimer disease. Prog Brain Res 101: 383–390
Van Leuven F (2000) Single and multiple transgenic mice as models for Alzheimer’s disease. Prog Neurobiol 61: 305–312
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: 735–741
Wolfe MS (2001a) Presenilin and gamma-secretase: structure meets function. J Neurochem 76:1615–1620
Wolfe MS (2001b) Secretase targets for Alzheimer’s disease: identification and therapeutic potential. J Med Chem 44: 2039–2060
Younkin SG (1995) Evidence that A(3 42 is the real culprit in Alzheimer’s disease. Ann Neurol 37: 287–288
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Permanne, B., Adessi, C., Fraga, S., Frossard, MJ., Saborio, G.P., Soto, C. (2002). Are β-sheet breaker peptides dissolving the therapeutic problem of Alzheimer’s disease?. In: Jellinger, K.A., Schmidt, R., Windisch, M. (eds) Ageing and Dementia Current and Future Concepts. Journal of Neural Transmission. Supplementa, vol 62. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6139-5_27
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DOI: https://doi.org/10.1007/978-3-7091-6139-5_27
Publisher Name: Springer, Vienna
Print ISBN: 978-3-211-83796-2
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