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β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer's therapy


Inhibition of cerebral amyloid β-protein deposition seems to be an important target for Alzheimer's disease therapy. Amyloidogenesis could be inhibited by short synthetic peptides designed as β-sheet breakers. Here we demonstrate a 5-residue peptide that inhibits amyloid βprotein fibrillogenesis, disassembles preformed fibrils in vitro and prevents neuronal death induced by fibrils in cell culture. In addition, the β-sheet breaker peptide significantly reduces amyloid βprotein deposition in vivo and completely blocks the formation of amyloid fibrils in a rat brain model of amyloidosis. These findings may provide the basis for a new therapeutic approach to prevent amyloidosis in Alzheimer's disease.

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  1. Soto, C., Branes, M.C., Alvarez, J. & Inestrosa, N.C. Structural determinants of the Alzheimer's amyloid beta-peptide. J Neurochem. 63, 1191–1198 (1994).

    Article  CAS  Google Scholar 

  2. Pike, C.J., Burdick, D., Walencewicz, A.J., Glabe, C.G. & Cotman, C.W. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state J. Neurosci. 13, 1676–1687 (1993).

    Article  CAS  Google Scholar 

  3. Lorenzo, A. & Yankner, B.A. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl. Acad. Sci. USA. 91, 12243–12247 (1994).

    Article  CAS  Google Scholar 

  4. Yankner, B.A. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron. 16, 921–932 (1996).

    Article  CAS  Google Scholar 

  5. Soto, C., Kindy, M.S., Baumann, M. & Frangione, B. Inhibition of Alzheimer's amyloidosis by peptides that prevent β-sheet conformation. Biochem. Biophys. Res. Commun. 226, 672–680 (1996).

    Article  CAS  Google Scholar 

  6. Soto, C., Castaño, E.M., Frangione, B. & Inestrosa, N.C. The alpha-helical to beta-strand transition in the amino-terminal fragment of the amyloid beta-peptide modulates amyloid formation. J. Biol. Chem. 270, 3063–3067 (1995).

    Article  CAS  Google Scholar 

  7. Hilsich, C., Kisters-Woike, B., Reed, J., Masters, C.L. & Beyreuther, K. Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer's disease βA4 peptides. J. Mol. Biol. 228, 460–473 (1992).

    Article  Google Scholar 

  8. Lee, J.P. et al. H-1 NMR of A-beta amyloid peptide congeners in water solution. Conformational changes correlate with plaque competence. Biochemistry 34, 5191–5200 (1995).

    Article  CAS  Google Scholar 

  9. Wood, J.D., Wetzel, R., Martin, J.D. & Hurle, M.R. Prolines and amyloidogenicity in fragments of the Alzheimer's peptide /A4. Biochemistry 34, 724–730 (1995).

    Article  CAS  Google Scholar 

  10. Chou, P.Y. & Fasman, G.D. Empirical predictions of protein conformation. Ann. Rev. Biochem. 47, 251–276 (1978).

    Article  CAS  Google Scholar 

  11. Soto, C., Castaño, E.M., Prelli, F., Kumar, R.A. & Baumann, M. Apolipoprotein E increases the fibrillogenic potential of synthetic peptides derived from Alzheimer's, gelsolin and AA amyloids. FEBS Letters 371, 110–114 (1995).

    Article  CAS  Google Scholar 

  12. Wood, S.J., 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 AP. J. Mol. Biol. 256, 870–877 (1996).

    Article  CAS  Google Scholar 

  13. Simmons, L.K. et al. Secondary structure of amyloid beta peptide correlates with neurotoxic activity in vitro. Mol. Pharmacol. 45, 373–379 (1994).

    CAS  PubMed  Google Scholar 

  14. Sigurdsson, E.M., Lorens, S.A., Hejna, M.J., Dong, X.W. & Lee, J.M. Local and distant histopathological effects of unilateral amyloid- 25–35 injections into the amygdala of young F344 rats. Neurobiol. Aging. 17, 893–901 (1996).

    Article  CAS  Google Scholar 

  15. Sigurdsson, E.M., Lee, J.M., Dong, X.W., Hejna, M.J. & Lorens, S.A. Bilateral injections of Amyloid-β 25–35 into the amygdala of young fischer rats: Behavioral, neurochemical and time dependent histopathological effects. Neurobiol. Aging 18, 591–608 (1997).

    Article  CAS  Google Scholar 

  16. Arriagada, P.V., Growdon, J.H., Hedley-Whyte, E.T. & Hyman, B.T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42, 631–639 (1992).

    Article  CAS  Google Scholar 

  17. Jimenez-Huete, A. et al. Antibodies directed to the carboxyl terminus of amyloid beta peptide recognize sequence epitopes and distinct immunoreactive deposits in Alzheimer's disease brain. Alzheimer's Report 1, 1–7 (1998).

    Google Scholar 

  18. Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F -amyloid precursor protein. Nature 373, 523–527 (1995).

    Article  CAS  Google Scholar 

  19. Hsiao, K.K. et al. Correlative memory deficits, A elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  20. Holcomb, L. et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nature Med. 4, 97–100 (1998).

    Article  CAS  Google Scholar 

  21. Glenner, G.G. Amyloid deposits and amyloidosis. The β-fibrilloses. N. Engl. J. Med. 302, 1283–1292 (1980).

    Article  CAS  Google Scholar 

  22. Lorenzo, A., Razzaboni, B., Weir, G.C. & Yankner, B.A. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 368, 756–760 (1994).

    Article  CAS  Google Scholar 

  23. Forloni, G. et al. Neurotoxicity of a prion protein fragment. Nature 362, 543–546 (1993).

    Article  CAS  Google Scholar 

  24. Esler, W.P. et al. Aβ deposition inhibitor screen using synthetic amyloid. Nature Biotechnol. 15, 258–263 (1997).

    Article  CAS  Google Scholar 

  25. Wisniewski, T., Ghiso, J. & Frangione, B. Alzheimer's disease and soluble Aβ. Neurobiol. Aging. 15, 143–152 (1994).

    Article  CAS  Google Scholar 

  26. Thomas, P.J., Qu, B. & Pedersen, P.L. Defective protein folding as a basis of human disease. Trends Biochem. Sci. 20, 456–459 (1995).

    Article  CAS  Google Scholar 

  27. Kelly, J.W. Alternative conformations of amyloidogenic proteins govern their behavior. Curr. Opin. Struct. Biol. 6, 11–17 (1996).

    Article  CAS  Google Scholar 

  28. Soto, C. et al. Reversal of disease-specific prion protein conformation and protease-resistance by peptides designed as β-sheet breakers. (Manuscript submitted).

  29. Janossy, G., Greaves, M.F., Doenhoff, M.J. & Snajder, J. Lymphocyte activation. Quantitation of the proliferative response to mitogens using defined T and B cell populations. Clin. Exp. Immunol. 14, 581 (1973).

  30. Duke, CR, et al. in Current Protocols in Immunology (eds. Coligan, J.E., Kruisbeek, A.M., Margulies, D.H., Shevach, E.M., and Strober, W) 17.1–17.33 (John Wiley & Sons, New York, 1995).

    Google Scholar 

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Soto, C., Sigurdsson, E., Morelli, L. et al. β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer's therapy. Nat Med 4, 822–826 (1998).

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