Amyloid Inhibitors and β-Sheet Breakers

  • Claudio Soto
  • Lisbell Estrada
Part of the Subcellular Biochemistry book series (SCBI, volume 38)

Abstract

Compelling evidence indicates that a key pathological event in Alzheimer’s disease is the misfolding and aggregation of normal soluble amyloid-β peptide into β-sheet-rich oligomeric structures which have a neurotoxic activity and ability to form insoluble amyloid deposits that accumulate in the brain. β-sheet breakers constitute a new class of drugs that are designed to specifically bind amyloid-β peptide blocking and/or reversing the misfolding process. In this article we review this approach and summarize the data supporting the view that β-sheet breakers could be serious candidates to combat this devastating disease.

Key words

Alzheimer’s disease amyloid β-sheet breakers therapy 

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References

  1. Adessi, C., Frossard, M.J., Boissard, C., Fraga, S., Bieler, S., Ruckle, T., Vilbois, F., Robinson, S.M., Mutter, M., Banks, W.A., and Soto, C., 2003, Pharmacological profiles of peptide drug candidates for the treatment of Alzheimer’s disease. J. Biol. Chem. 278: 13905–13911.PubMedCrossRefGoogle Scholar
  2. Adessi, C. and Soto, C., 2002, Converting a peptide into a drug: Strategies to improve stability and bioavailability. Curr. Med. Chem. 9: 963–978.PubMedCrossRefGoogle Scholar
  3. Allsop, D., Gibson G., Martin, I.K., Moore S., Turnbull, S., and Twyman, L.J., 2001, 3-p-Toluoyl-2-[4′-(3-diethylaminopropoxy)-phenyl]-benzofuran and 2-[4′-(3-diethylaminopropoxy)-phenyl]-benzofuran do not act as surfactants or micelles when inhibiting the aggregation of beta-amyloid peptide. Bioorg. Med. Chem. Lett. 11: 255–257.PubMedCrossRefGoogle Scholar
  4. Caughey, B. and Lansbury, P.T., 2003, Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26: 267–298.PubMedCrossRefGoogle Scholar
  5. Cherny, R.A., Atwood, C.S., Xilinas, M.E., Gray, D.N., Jones, W.D., McLean, C.A., Barnham, K.J., Volitakis, I., Fraser, F.W., Kim, Y., Huang, X., Goldstein, L.E., Moir, R.D., Lim, J.T., Beyreuther, K., Zheng, H., Tanzi, R.E., Masters, C.L., and Bush, A.L, 2001, Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30: 665–676.PubMedCrossRefGoogle Scholar
  6. De Felice, F.G., Houzel, J.C., Garcia-Abreu, J., Louzada, P.R., Jr., Afonso, R.C., Meirelles, M.N., Lent, R., Neto, V.M., and Ferreira, S.T., 2001, Inhibition of Alzheimer’s disease beta-amyloid aggregation, neurotoxicity, and in vivo deposition by nitrophenols: implications for Alzheimer’s therapy. FASEB J. 15: 1297–1299.PubMedGoogle Scholar
  7. Dewachter, I., Van Dorpe, J., Smeijers, L., Gilis, M., Kuiperi, C., Laenen, I., Caluwaerts, N., Moechars, D., Checler, F., Vanderstichele, H., and Van Leuven, F., 2000, Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilinl. J. Neurosci. 20: 6452–6458.PubMedGoogle Scholar
  8. Findeis, M.A., 2002, Peptide inhibitors of beta amyloid aggregation. Curr. Top. Med. Chem. 2: 417–423.PubMedCrossRefGoogle Scholar
  9. Findeis, M.A., Lee, J.J., Kelley, M., Wakefield, J.D., Zhang, M.H., Chin, J., Kubasek, W., and Molineaux, S.M., 2001, Characterization of cholyl-leu-val-phe-phe-ala-OH as an inhibitor of amyloid beta-peptide polymerization. Amyloid. 8: 231–241.PubMedGoogle Scholar
  10. Findeis, M.A., Musso, G.M., Arico-Muendel, C.C., Benjamin, H.W., Hundal, A.M., Lee, J.J., Chin, J., Kelley, M., Wakefield, J., Hayward, N.J., and Molineaux, S.M., 1999, Modified-peptide inhibitors of amyloid beta-peptide polymerization. Biochemistry 38: 6791–6800.PubMedCrossRefGoogle Scholar
  11. Forloni, G., Colombo, L., Girola, L., Tagliavini, F., and Salmona, M., 2001, Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett. 487: 404–407.PubMedCrossRefGoogle Scholar
  12. Fraser, P.E., Yang, D.S., Yu, G., Levesque, L., Nishimura, M., Arawaka, S., Serpell, L.C., Rogaeva, E., and George-Hyslop, P., 2000, Presenilin structure, function and role in Alzheimer disease. Biochim. Biophys. Acta 1502: 1–15.PubMedGoogle Scholar
  13. Gervais, F., Chalifour, R., Garceau, D., Kong, X., Laurin J., Mclaughlin, R., Morissette, C., and Paquette, J., 2001, Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. Amyloid. 8Suppl 1: 28–35.PubMedGoogle Scholar
  14. Ghanta, J., Shen, C.L., Kiessling, L.L., and Murphy, R.M., 1996, A strategy for designing inhibitors of beta-amyloid toxicity. J. Biol. Chem. 271: 29525–29528.PubMedCrossRefGoogle Scholar
  15. Gordon, D.J., Sciarretta, K.L., and Meredith, S.C., 2001, Inhibition of beta-amyloid(40) fibrillogenesis and disassembly of beta-amyloid(40) fibrils by short beta-amyloid congeners containing N-methyl amino acids at alternate residues. Biochemistry 40: 8237–8245.PubMedCrossRefGoogle Scholar
  16. Hardy, J., Duff, K., Hardy, K.G., Perez-Tur, J., and Hutton, M., 1998, Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat. Neurosci. 1: 355–358.PubMedCrossRefGoogle Scholar
  17. Hilbich, C., Kisters-Woike, B., Reed, J., Masters, C.L., and Beyreuther, K., 1992, Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer’s disease beta A4 peptides. J. Mol. Biol. 228: 460–473.PubMedCrossRefGoogle Scholar
  18. Hosoda, T., Nakajima, H., and Honjo, H., 2001, Estrogen protects neuronal cells from amyloid beta-induced apoptotic cell death. Nenroreport 12: 1965–1970.CrossRefGoogle Scholar
  19. Hughes, E., Burke R.M., and Doig, A.J., 2000, Inhibition of toxicity in the beta-amyloid peptide fragment beta-(25—35) using N-methylated derivatives: a general strategy to prevent amyloid formation. J. Biol. Chem. 275: 25109–25115.PubMedCrossRefGoogle Scholar
  20. Kapurniotu, A., Buck, A., Weber, M., Schmauder, A., Hirsch, T., Bernhagen, J., and Tatarek-Nossol, M., 2003, Conformational restriction via cyclization in beta-amyloid peptide Abeta(l–28) leads to an inhibitor of Abeta(l–28) amyloidogenesis and cytotoxicity. Chem. Biol. 10: 149–159.PubMedCrossRefGoogle Scholar
  21. Kim, C.A. and Berg, J.M., 1993, Thermodynamic beta-sheet propensities measured using a zinc-finger host peptide. Nature 362: 270.Google Scholar
  22. Kisilevsky, R., Lemieux, L.J., Fraser, P.E., Kong, X., Hultin, P.G., and Szarek, W.A., 1995, Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer’s disease. Nat. Med. 1: 143–148.PubMedCrossRefGoogle Scholar
  23. Lambert, M.P., Barlow, A.K., Chromy, B.A., Edwards, C., Freed, R., Liosatos, M., Morgan, T.E., Rozovsky, I., Trommer, B., Viola, K.L., Wals, P., Zhang, C., Finch, C.E., Krafft, G.A., and Klein, W.L., 1998, Diffusible, nonfibrillar ligands derived from Abetal-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95: 6448–6453.PubMedCrossRefGoogle Scholar
  24. Lim, G.P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., Tran, T., Ubeda, O., Ashe, K.H., Frautschy, S.A., and Cole, G.M., 2000, Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J. Neurosci. 20: 5709–5714.PubMedGoogle Scholar
  25. Lorenzo, A. and Yankner, B.A., 1994, Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc. Natl. Acad. Sci. USA 91: 12243–12247.PubMedCrossRefGoogle Scholar
  26. Mann, D.M., 1989, Cerebral amyloidosis, ageing and Alzheimer’s disease; a contribution from studies on Down’s syndrome. Neurobiol. Aging 10: 397–399.PubMedCrossRefGoogle Scholar
  27. Mason, J.M., Kokkoni, N., Stott, K., and Doig, A.J., 2003, Design strategies for anti-amyloid agents. Curr. Opin. Struct Biol. 13: 526–532.PubMedCrossRefGoogle Scholar
  28. McGeer, E.G. and McGeer, P.L., 1998, The importance of inflammatory mechanisms in Alzheimer disease. Exp. Gerontol. 33: 371–378.PubMedCrossRefGoogle Scholar
  29. Merlini, G., Ascari, E., Amboldi, N., Bellotti, V., Arbustini, E., Perfetti, V., Ferrari, M., Zorzoli, I., Marinone, M.G., and Garini, P., 1995, Interaction of the anthracycline 4′-iodo-4′-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis. Proc. Natl. Acad. Sci. USA 92: 2959–2963.PubMedCrossRefGoogle Scholar
  30. Moechars, D., Dewachter, I., Lorent, K., Reverse, D., Baekelandt, V., Naidu, A., Tesseur, I., Spittaels, K., Haute, C.V., Checler, F., Godaux, E., Cordell, B., and Van Leuven, F., 1999, Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J. Biol. Chem. 274: 6483–6492.PubMedCrossRefGoogle Scholar
  31. Moore, G.J., 1994, Designing peptide mimetics, Trends Pharmacol. Sci. 15: 124–129.PubMedCrossRefGoogle Scholar
  32. Nakagami, Y., Nishimura, S., Murasugi, T., Kaneko, I., Meguro, M., Marumoto, S., Kogen, H., Koyama, K., and Oda, T., 2002, A novel beta-sheet breaker, RS-0406, reverses amyloid beta-induced cytotoxicity and impairment of long-term potentiation in vitro. Br. J. Pharmacol. 137: 676–682.PubMedCrossRefGoogle Scholar
  33. Pallitto, M.M., Ghanta, J., Heinzelman, P., Kiessling, L.L., and Murphy, R.M., 1999, Recognition sequence design for peptidyl modulators of beta-amyloid aggregation and toxicity. Biochemistry 38: 3570–3578.PubMedCrossRefGoogle Scholar
  34. Pappolla, M., Bozner, P., Soto, C., Shao, H., Robakis, N.K., Zagorski, M., Frangione, B., and Ghiso, J., 1998, Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J. Biol. Chem. 273: 7185–7188.PubMedCrossRefGoogle Scholar
  35. Permanne, B., Adessi, C., Fraga, S., Frossard, M.J., Saborio, G.P., and Soto, C., 2002a, Are beta-sheet breaker peptides dissolving the therapeutic problem of Alzheimer’s disease? J. Neural Transm. Suppl 293–301.Google Scholar
  36. Permanne, B., Adessi, C., Saborio, G.P., Fraga, S., Frossard, M.J., Van Dorpe, J., Dewachter, I., Banks, W.A., Van Leuven, F., and Soto, C., 2002b, Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer’s disease by treatment with a beta-sheet breaker peptide. FASEB J. 16: 860–862.PubMedGoogle Scholar
  37. Pike, C.J., Burdick, D., Walencewicz, A.J., Glabe, C.G., and Cotman, C.W., 1993, Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J. Neurosci. 13: 1676–1687.PubMedGoogle Scholar
  38. Price, D.L., Tanzi, R.E., Borchelt, D.R., and Sisodia, S.S., 1998, Alzheimer’s disease: genetic studies and transgenic models. Anna. Rev. Genet. 32: 461–493.CrossRefGoogle Scholar
  39. Salomon, A.R., Marcinowski, K.J., Friedland, R.P., and Zagorski, M.G., 1996, Nicotine inhibits amyloid formation by the beta-peptide. Biochemistry 35: 13568–13578.PubMedCrossRefGoogle Scholar
  40. Selkoe, D.J., 1997, Alzheimer’s disease: genotypes, phenotypes, and treatments. Science 275: 630–631.PubMedCrossRefGoogle Scholar
  41. Selkoe, D.J., 2000a, The genetics and molecular pathology of Alzheimer’s disease: roles of amyloid and the presenilins. Neurol. Clin. 18: 903–922.PubMedCrossRefGoogle Scholar
  42. Selkoe, D.J., 2000b, The origins of Alzheimer disease-A is for amyloid. Jama: Journal of the American Medical Association 283: 1615–1617.PubMedCrossRefGoogle Scholar
  43. Sigurdsson, E.M., Permanne, B., Soto, C., Wisniewski, T., and Frangione, B., 2000, In vivo reversal of amyloid-beta lesions in rat brain. J. Nenropathol. Exp. Neurol. 59: 11–17.Google Scholar
  44. Soto, C., 1999, Plaque busters: strategies to inhibit amyloid formation in Alzheimer’s disease. Mol. Med. Today 5: 343–350.PubMedCrossRefGoogle Scholar
  45. Soto, C., 2003, Unfolding the role of Protein Misfolding in Neurodegenerative Diseases. Nature Rev. Neurosci. 4: 49–60.CrossRefGoogle Scholar
  46. Soto, C., Branes, M.C., Alvarez, J., and Inestrosa, N.C., 1994, Structural determinants of the Alzheimer’s amyloid beta-peptide. J. Neurochem. 63: 1191–1198.PubMedCrossRefGoogle Scholar
  47. Soto, C., Castano, E.M., Frangione, B., and Inestrosa, N.C., 1995, 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.PubMedCrossRefGoogle Scholar
  48. Soto, C., Kindy, M.S., Baumann, M., and Frangione, B., 1996, Inhibition of Alzheimer’s amyloidosis by peptides that prevent beta-sheet conformation. Biochem. Biophys. Res. Commun. 226: 672–680.PubMedCrossRefGoogle Scholar
  49. Soto, C., Sigurdsson, E.M., Morelli, L., Kumar, R.A., Castano, E.M., and Frangione, B., 1998, Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer’s therapy. Nature Med. 4: 822–826.PubMedCrossRefGoogle Scholar
  50. Terry, R.D., 1994, Neuropathological changes in Alzheimer disease. Prog. Brain Res. 101: 383–390.PubMedCrossRefGoogle Scholar
  51. Tjernberg, L.O., Naslund, J., Lindqvist, F., Johansson, J., Karlstrom, A.R., Thyberg, J., Terenius, L., and Nordstedt, C., 1996, Arrest of beta-amyloid fibril formation by a pentapeptide ligand. J. Biol. Chem. 271: 8545–8548.PubMedCrossRefGoogle Scholar
  52. Tomiyama, T., Asano, S., Suwa, Y., Morita, T., Kataoka, K., Mori, H., and Endo, N., 1994, Rifampicin prevents the aggregation and neurotoxicity of amyloid beta protein in vitro. Biochem. Biophys. Res. Commun. 204: 76–83.PubMedCrossRefGoogle Scholar
  53. Van Leuven, F., 2000, Single and multiple transgenic mice as models for Alzheimer’s disease. Progress in Neurobiology 61: 305–312.PubMedCrossRefGoogle Scholar
  54. Walsh, D.M., Hartley, D., Kusumoto, Y., Fezoui, Y., Condrom, M.M., Lomakin, A., Benedek, G.B., Selkoe, D.J., and Teplow, D.B., 1999, Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J. Biol. Chem. 274: 25945–25952.PubMedCrossRefGoogle Scholar
  55. Walsh, D.M., Klyubin, I., Fadeeva, J.V., Rowan, M.J., and Selkoe, D.J., 2002, Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem. Soc. Trans. 30: 552–557.PubMedCrossRefGoogle Scholar
  56. Wood, S.J., MacKenzie, L., Maleeff, B., Hurle, M.R., and Wetzel, R., 1996, Selective inhibition of Aβ fibril formation. J. Biol. Chem. 271: 4086–4092.PubMedCrossRefGoogle Scholar
  57. Wood, S.J., Wetzel, R., Martin, J.D., and Hurle, M.R., 1995, Prolines and amyloidogenicity in fragments of the Alzheimer’s peptide beta/A4. Biochemistry 34: 724–730.PubMedCrossRefGoogle Scholar
  58. Yankner, B.A., 1996, Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 16: 921–932.PubMedCrossRefGoogle Scholar
  59. Younkin, S.G., 1995, Evidence that Aβ 42 is the real culprit in Alzheimer’s disease. Ann. Neurol. 37: 287–288.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Claudio Soto
    • 1
  • Lisbell Estrada
    • 1
  1. 1.Protein Misfolding Disorders Laboratory, Department of NeurologyUniversity of Texas Medical BranchGalvestonUSA

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