Amyloid Accumulation and Pathogensis of Alzheimer’s Disease: Significance of Monomeric, Oligomeric and Fibrillar Aβ

  • Charles C. Glabe
Part of the Subcellular Biochemistry book series (SCBI, volume 38)


This chapter reviews recent findings that indicate that soluble amyloid oligomers may represent the primary pathological species in Alzheimer’s and other degenerative diseases. Various amyloids share a number of common properties, including their structures and pathways for fibril formation and accumulation in disease. Recent findings suggest that toxic amyloid oligomers share a common structure, suggesting that they also share a common mechanism of pathogenesis

Key words

Amyloid Aβ oligomer fibril pathogenic mechanisms 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anguiano, M, Nowak R.J., and Lansbury, P.T. Jr, 2002, Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes. Biochemistry 41: 11338–11343.PubMedCrossRefGoogle Scholar
  2. Antzutkin, O.N., Leapman, R.D., Balbach, J.J., and Tycko, R., 2002, Supramolecular structural constraints on Alzheimer’s beta-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry 41:15436–15450.PubMedCrossRefGoogle Scholar
  3. Balbach, J.J., Petkova, A.T., Oyler, N.A., Antzutkin, O.N., Gordon, D.J., Meredith, S.C., and Tycko, R., 2002, 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. 83: 1205–1216.PubMedGoogle Scholar
  4. Bendiske, J., and Bahr, B.A., 2003, Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis—an approach for slowing Alzheimer disease?. J. Neuropathol. Exp. Neurol. 62: 451–463.PubMedGoogle Scholar
  5. Benzinger, T.L., Gregory, D.M., Burkoth, T.S., Miller-Auer, H., Lynn, D.G., Botto, R.E., and Meredith, S.C., 1998, Propagating structure of Alzheimer’s beta-amyloid(10–35) is parallel beta-sheet with residues in exact register. Proc. Natl. Acad. Sci. USA 95: 13407–13412.PubMedCrossRefGoogle Scholar
  6. Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., Taddei, N., Ramponi, G., Dobson, C.M., and Stefani,. M., 2002, Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416: 507–511.PubMedCrossRefGoogle Scholar
  7. Burdick, D., Soreghan, B., Kwon, M., Kosmoski, J., Knauer, M., Henschen, A., Yates, J., Cotman, C., and Glabe. C., 1992, Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. J. Biol. Chem. 267: 546–554.PubMedGoogle Scholar
  8. Caughey, B., and Lansbury, P.T., 2003, Protoftbrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Ann. Rev. Neurosci. 26: 267–298.PubMedCrossRefGoogle Scholar
  9. Dahlgren, K.N., Manelli, A.M., Stine, W.B Jr., Baker, L.K., Krafft, G.A., and LaDu, M.J.. 2002, Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J. Biol. Chem. 277: 32046–32053.PubMedCrossRefGoogle Scholar
  10. Der-Sarkissian, A., Jao, C.C., Chen, J., and Langen, R., 2003, Structural organization of alpha-synuclein fibrils studied by site-directed spin labeling. J Biol Chem. 278:37530–5.PubMedCrossRefGoogle Scholar
  11. Dobson, C.M., 1999., Protein misfolding, evolution and disease. TIBS. 24: 3293–32.Google Scholar
  12. Esler, W.P., Stimson, E.R., Jennings, J.M., Vinters, H.V., Ghilardi, J.R., Lee, J.P., Mantyh, P.W., and Maggio, J.E., 2000, Alzheimer’s disease amyloid propagation by a template-dependent dock-lock mechanism. Biochemistry 39: 6288–6295.PubMedCrossRefGoogle Scholar
  13. Fandrich, M., and Dobson, C.M., 2002, The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation. EMBO J. 21: 5682–5690.PubMedCrossRefGoogle Scholar
  14. Garzon-Rodriguez, W., Sepulveda-Becerra, M., Milton, S., and Glabe, C.G., 1997, Soluble amyloid Abeta-(l–40) exists as a stable dimer at low concentrations. J Biol Chem. 272: 21037–21044.PubMedCrossRefGoogle Scholar
  15. Garzon-Rodriguez, W., Vega, A., Sepulveda-Becerra, M., Milton, S., Johnson, D.A., Yatsimirsky, A.K., and Glabe, C.G., 2000, A conformation change in the carboxyl terminus of Alzheimer’s Abeta (1-40) accompanies the transition from dimer to fibril as revealed by fluorescence quenching analysis. J. Biol. Chem. 275: 22645–22649.PubMedCrossRefGoogle Scholar
  16. Gong, Y., Chang, L., Viola, K.L, Lacor, P.N., Lambert, M.P., Finch, C.E., Krafft, G.A., and Klein, W.L., 2003, 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. 100: 10417–10422.PubMedCrossRefGoogle Scholar
  17. Gregori, L., Fuchs, C, Figueiredo-Pereira, M.E., Van Nostrand, W.E., and Goldgaber, D., 1995, Amyloid beta-protein inhibits ubiquitin-dependent protein degradation in vitro. J. Biol. Chem. 270: 19702–19708.PubMedCrossRefGoogle Scholar
  18. Hajimohammadreza, I., Anderson, V.E., Cavanagh, J.B., Seville, M.P., Nolan, C.C., Anderton, B.H., and Leigh, P.N., 1994, beta-Amyloid precursor protein fragments and lysosomal dense bodies are found in rat brain neurons after ventricular infusion of leupeptin. Brain Res. 640: 25–32.PubMedCrossRefGoogle Scholar
  19. Hardy, J., and Selkoe. D.J., 2002, The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297: 353–356.PubMedCrossRefGoogle Scholar
  20. Harper, J.D., Lieber, C.M., and Lansbury, P.T. 1997a, Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer’s disease amyloid-beta protein. Chem. Biol. 4: 951–959.PubMedCrossRefGoogle Scholar
  21. Harper, J.D., Wong, S.S., Lieber, C.M., and Lansbury, P.T., 1997b, Observation of metastable Abeta amyloid protofibrils by atomic force microscopy. Chem Biol. 4: 119–125.PubMedCrossRefGoogle Scholar
  22. Hartley, D.M., Walsh, D.M, Ye, C.P., Diehl, T., Vasquez, S., Vassilev, P.M., Teplow D.B., and Selkoe. D.J., 1999, Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J. Neurosci. 19: 8876–8884.PubMedGoogle Scholar
  23. Hilbich, C., Kisters-Woike, B., Reed, J., Masters, C.L., and Beyreuther, K., 1991, Aggregation and secondary structure of synthetic amyloid beta A4 peptides of Alzheimer’s disease. J. Mol. Biol. 218: 149–163.PubMedCrossRefGoogle Scholar
  24. Houlden, H., Baker, M., McGowan, E., Lewis, P., Hutton, M., Crook, R., Wood, N.W., Kumar-Singh, S., Geddes, J., Swash, M., Scaravilli, F., Holton, J.L., Lashley, T., Tomita, T., Hashimoto, T., Verkkoniemi, A., Kalimo, H., Somer, M., Paetau, A., Martin, J.J., Van Broeckhoven, C, Golde, T., Hardy, J., Haltia, M., and Revesz, T., 2000, Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann. Neurol. 48: 806–808.PubMedCrossRefGoogle Scholar
  25. Hsia, A.Y., Masliah, E., McConlogue, L., Yu, G.Q., Tatsuno, G., Hu, K., Kholodenko, D., Malenka, R.C., Nicoll, R.A., and Mucke, L., 1999, Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc. Natl. Acad. Sci. USA 96: 3228–3233.PubMedCrossRefGoogle Scholar
  26. Kagan, B.L., Hirakura, Y., Azimov, R., Azimova, R., and Lin M.C., 2002, The channel hypothesis of Alzheimer’s disease: current status. Peptides. 23: 1311–1315.PubMedCrossRefGoogle Scholar
  27. Kayed, R., Head, E., Thompson, J.L., McIntire, T.M., Milton, S.C., Cotman, C.W., and Glabe, C.G., 2003, Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300: 486–489.PubMedCrossRefGoogle Scholar
  28. Keck, S., Nitsch, R., Grune, T., and Ullrich, O., 2003, Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease. J. Neurochem. 85: 115–122.PubMedCrossRefGoogle Scholar
  29. Kirkitadze, M.D., Bitan, G., and Teplow. D.B., 2002, Paradigm shifts in Alzheimer’s disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J. Neurosci. Res. 69: 567–577.PubMedCrossRefGoogle Scholar
  30. Klein, W.L., Krafft, G.A., and Finch, C.E., 2001, Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci. 24: 219–224.PubMedCrossRefGoogle Scholar
  31. Kuo, Y.M., Emmerling, M.R., Vigo-Pelfrey, C., Kasunic, T.C., Kirkpatrick, J.B., Murdoch, G.H., Ball, M.J., and Roher, A.E., 1996, Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J. Biol. Chem. 271: 4077–4081.PubMedCrossRefGoogle Scholar
  32. Lashuel, H.A., Hartley, D., Petre, B.M., Walz, T., and Lansbury, P.T. Jr., 2002, Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418: 291.PubMedCrossRefGoogle Scholar
  33. LeVine, H., 2002, 4,4(′)-Dianilino-l,l(′)-binaphthyl-5,5(′)-disulfonate: report on non-beta-sheet conformers of Alzheimer’s peptide beta (l–40). Arch. Biochem, Biophys. 404: 106–115.CrossRefGoogle Scholar
  34. LeVine, H.D., 1993, Thioflavinee T interaction with synthetic Alzheimer’s disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci. 2: 404–410.PubMedCrossRefGoogle Scholar
  35. Lomakin, A., Teplow, D.B., Kirschner, D.A., and Benedek, G.B., 1997. Kinetic theory of fibrillogenesis of amyloid beta-protein. Proc. Natl. Acad. Sci. USA 94: 7942–7947.PubMedCrossRefGoogle Scholar
  36. Lue, L.F., Kuo, Y.M., Roher, A.E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J.H., Rydel, R.E., and Rogers, J., 1999, Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Amer. J. Pathol. 155: 853–862.Google Scholar
  37. Mattson, M.P., 2002, Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer’s disease. J. Neurovirol. 8: 539–550.PubMedCrossRefGoogle Scholar
  38. McLean, C.A., Cherny, R.A., Fraser, F.W., Fuller, S.J., Smith, M.J., Beyreuther, K., Bush, A.I., and Masters. C.L., 1999, Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neural. 46: 860–866.CrossRefGoogle Scholar
  39. Petkova, A.T., Buntkowsky, G., Dyda, F., Leapman, R.D., Yau, W.M., and Tycko, R., 2004, Solid State NMR Reveals a pH-dependent Antiparallel beta-Sheet Registry in Fibrils Formed by a beta-Amyloid Peptide. J. Mol. Biol. 335: 247–260.PubMedCrossRefGoogle Scholar
  40. Pitschke, M., Prior, R., Haupt, M., and Riesner, D., 1998, Detection of single amyloid beta-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy [see comments]. Nature Med. 4: 832–834.PubMedCrossRefGoogle Scholar
  41. Shen, C.L., and Murphy, R.M., 1995, Solvent effects on self-assembly of beta-amyloid peptide. Biophys. J. 69: 640–651.PubMedGoogle Scholar
  42. Soreghan, B., Kosmoski, J., and Glabe, C., 1994, Surfactant properties of Alzheimer’s A beta peptides and the mechanism of amyloid aggregation. J. Biol. Chem. 269: 28551–28554.PubMedGoogle Scholar
  43. Terry, R.D., 1996, The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J. Neuropathol Exp. Neurol. 55: 1023–1025.PubMedCrossRefGoogle Scholar
  44. Torok, M., Milton, S., Kayed, R., Wu, P., McIntire, T., Glabe, C.C., and Langen, R., 2002, Structural and dynamic features of Alzheimer’s Abeta peptide in amyloid fibrils studied by site-directed spin labeling. J. Biol. Chem. 277: 40810–40815.PubMedCrossRefGoogle Scholar
  45. Tseng, B.P., Esler, W.P., Clish, C.B., Stimson, E.R., Ghilardi, J.R., Vinters, H.V., Mantyh, P.W., Lee, J.P., and Maggio, J.E., 1999, Deposition of monomeric, not oligomeric, Abeta mediates growth of Alzheimer’s disease amyloid plaques in human brain preparations. Biochemistry 38: 10424–10431.PubMedCrossRefGoogle Scholar
  46. Verkkoniemi, A., Somer, M., Rinne, J.O., Myllykangas, L., Crook, R., Hardy, J., Viitanen, M., Kalimo, H., and Haltia, M., 2000, Variant Alzheimer’s disease with spastic paraparesis: clinical characterization. Neurology 54: 1103–1109.PubMedGoogle Scholar
  47. Waelter, S., Boeddrich, A., Lurz, R., Scherzinger, E., Lueder, G., Lehrach, H., and Wanker, E.E., 2001, Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol. Biol. Cell 12: 1393–1407.PubMedGoogle Scholar
  48. 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
  49. Walsh, D.M., Lomakin, A., Benedek, G.B., Condron, M.M., and Teplow, D.B., 1997, Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J. Biol. Chem. 272: 22364–22372.PubMedCrossRefGoogle Scholar
  50. Westerman, M.A., Cooper-Blacketer, D., Mariash, A., Kotilinek, L., Kawarabayashi, T., Younkin, L.H., Carlson, G.A., Younkin, S.G., and Ashe, K.H., 2002, The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J. Neurosci. 22: 1858–1867.PubMedGoogle Scholar
  51. Zagorski, M.G., Yang, J., Shao, H., Ma, K., Zeng, H., and Hong, A., 1999, Methodological and chemical factors affecting amyloid beta peptide amyloidogenicity. Meth. Enzymol. 309: 189–204.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Charles C. Glabe
    • 1
  1. 1.University of California, IrvineIrvineUSA

Personalised recommendations