NeuroMolecular Medicine

, Volume 4, Issue 1–2, pp 49–58 | Cite as

Interactions of amyloidogenic proteins

  • Benoit I. Giasson
  • Virginia M. Y. Lee
  • John Q. TrojanowskiEmail author


The various protein deposits of brain amyloidosis share common ultrastructural, biophysical, and histological properties. These amyloidogenic deposits can be composed of distinct proteins, which are conceptually associated with different neurodegenerative diseases. Amyloidogenic proteins are typically soluble monomeric precursors, which undergo remarkable conformation changes associated with the polymerization into 8− to 10−nm wide fibrils, which culminate in the formation of amyloid aggregates. Some amyloidogenic inclusions are extracellular, such as senile plaques of Alzheimer’s disease, which are composed of amyloid β (Aβ) peptides. However, intracytoplasmic amyloid aggregates, such as neurofibrillary tangles in Alzheimer’s disease and Lewy bodies in Parkinson’s disease, are composed of the proteins tau and α-synuclein, respectively. The mounting awareness that the latter proteins are directly linked to the etiology of spectrum of neurodegenerative diseases has resulted in the coining of the terms “tauopathies” and “synucleinopathies.” However, emerging evidence for the overlap in the pathological and clinical features of patients with brain amyloidosis suggests that they may be linked mechanistically. Recently, it was demonstrated that α-synuclein, which has the ability to readily form amyloid in vitro without the need of other co-factors, can initiate tau amyloid formation. Following this initiation step, α-synuclein and tau can synergize the polymerization of each other. Furthermore, increased levels of Aβ peptides in brain can promote the formation of intracellular tau and α-synuclein amyloid aggregates, although the mechanism for this process is still unclear. These results indicate that the formation of amyloid composed of different proteins can affect each other directly or indirectly, likely contributing to the overlap in clinical and pathological features.

Index Entries

Aβ peptide Alzheimer’s disease amyloid Parkinson’s disease synuclein tau 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abe H., Yagishita S., Amano N., et al. (1992) Argyrophilic glial intracytoplasmic inclusions in multiple system atrophy: immunocytochemical and ultrastructural study. Acta Neuropathol. (Berl.) 84, 273–277.CrossRefGoogle Scholar
  2. Arrasate M., Perez M., Armas-Portela R., and Avila J. (1999) Polymerization of tau peptides into fibrillar structures. The effect of FTDP-17 mutations. FEBS Lett. 446, 199–202.PubMedCrossRefGoogle Scholar
  3. Athanassiadou A., Voutsinas G., Psiouri L., et al. (1999) Genetic analysis of families with Parkinson disease that carry the Ala53Thr mutation in the gene encoding alpha-synuclein. Am. J. Hum. Genet. 65, 555–558.PubMedCrossRefGoogle Scholar
  4. Bergeron C. and Pollanen M. (1989) Lewy bodies in Alzheimer disease—one or two diseases? Alzheimer Dis. Assoc. Disord. 3, 197–204.PubMedGoogle Scholar
  5. Berriman J., Serpell L. C., Oberg K. A., et al. (2003) Tau filaments from human brain and from in vitro assembly of recombinant protein show cross-β structure. Proc. Natl. Acad. Sci. USA 100, 9034–9038.PubMedCrossRefGoogle Scholar
  6. Boller F., Mizutani T., Roessmann U., and Gambetti P. (1980) Parkinson disease, dementia, and Alzheimer disease: clinicopathological correlations. Ann. Neurol. 7, 329–335.PubMedCrossRefGoogle Scholar
  7. Brée L., Bussière T., Buée-Scherrer V., Delacourte A., and Hof, P. R. (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Rev. 33, 95–130.CrossRefGoogle Scholar
  8. Cabin D. E., Shimazu K, Murphy D., et al. (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α-synuclein. J. Neurosci. 22, 8797–8807.PubMedGoogle Scholar
  9. Cairns N. J., Atkinson P. F., Hanger D. P., et al. (1997) Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer’s disease. Neurosci. Lett. 230, 49–52.PubMedCrossRefGoogle Scholar
  10. Conway K. A., Harper J. D., and Lansbury P.T. (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 4, 1318–1320.PubMedCrossRefGoogle Scholar
  11. Davidson W. S., Jonas A., Clayton D. F., and George J. M. (1998) Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 273, 9443–9449.PubMedCrossRefGoogle Scholar
  12. Ditter S. M. and Mirra S. S. (1987) Neuropathologic and clinical features of Parkinson’s disease in Alzheimer’s disease patients. Neurology 37, 754–760.PubMedGoogle Scholar
  13. Duda J. E., Giasson B. I., Mabon M. E., et al. (2002) Concurrence of α-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol. (Berl.) 104, 7–11.CrossRefGoogle Scholar
  14. Duda J. E., Lee V. M.-Y., and Trojanowski, J. Q. (2000) Neuropathology of synuclein aggregates. J. Neurosci. Res. 61, 121–127.PubMedCrossRefGoogle Scholar
  15. Forman M. S., Lee V.M.-Y., and Trojanowski J. Q. (2000) New insights into genetic and molecular mechanisms of brain degeneration in tauopathies. J. Chem. Neuroanat. 20, 225–244.PubMedCrossRefGoogle Scholar
  16. Forman M. S., Schmidt M. L., Kasturi S., et al. (2002) Tau and α-synuclein pathology in amygdala of parkinsism-dementia complex pateints of Guam. Am. J. Pathol. 160, 1725–1731.PubMedGoogle Scholar
  17. Galasko D., Hansen L. A., Katzman R., et al. (1994) Clinical-neuropathological correlations in Alzheimer’s disease and related dementias. Arch. Neurol. 51, 888–895.PubMedGoogle Scholar
  18. Gaspar P. and Gray F. (1984) Dementia in idiopathic Parkinson’s disease. A neuropathological study of 32 cases. Acta Neuropathol. (Berl.) 64, 43–52.CrossRefGoogle Scholar
  19. George J. M., Jin H., Woods W. S., and Clayton D. F. (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15, 361–372.PubMedCrossRefGoogle Scholar
  20. Giasson B. I. Forman M. S., Golbe L. I., et al. (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300, 636–640.PubMedCrossRefGoogle Scholar
  21. Giasson B. I. and Lee V. M.-Y. (2003) Are ubiquitination pathways central to Parkinson’s disease? Cell 114, 1–8.PubMedCrossRefGoogle Scholar
  22. Giasson B. I., Murray I. V., Trojanowski J. Q., and Lee V.M.-Y. (2001) A hydrophobic stretch of 12 amino acid residues in the middle of alpha- synuclein is essential for filament assembly. J. Biol. Chem. 276, 2380–2386.PubMedCrossRefGoogle Scholar
  23. Giasson B. I., Uryu K., Trojanowski J. Q., and Lee V.M.-Y. (1999) Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro. J. Biol. Chem. 274, 7619–7622.PubMedCrossRefGoogle Scholar
  24. Glenner G. G. (1980) Amyloid deposits and amyloidosis. N. Engl. J. Med. 302, 1283–1292.PubMedCrossRefGoogle Scholar
  25. Goedert M. (2001) Alpha-synuclein and neurodegenerative diseases. Nat. Rev. Neurosci. 2, 492–501.PubMedCrossRefGoogle Scholar
  26. Goedert M., Jakes R., and Crowther R. A. (1999) Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments. FEBS Lett. 450, 306–311.PubMedCrossRefGoogle Scholar
  27. Goedert M., Jakes R., Spillantini M. G., et al. (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553.PubMedCrossRefGoogle Scholar
  28. Goldberg M. S. and Lansbury P. T. (2000) Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson’s disease? Nat. Cell Biol. 2, E115-E119.PubMedCrossRefGoogle Scholar
  29. Götz J., Chen F., van Dorpe J., and Nitsch, R. M. (2001) Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ fibrils. Science 293, 1491–1495.PubMedCrossRefGoogle Scholar
  30. Gutekust C. A., Li S.-H., Yi H., et al. (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J. Neurosci. 19, 2522–2534.Google Scholar
  31. Hakim A. M. and Mathieson G. (1979) Dementia in Parkinson disease: a neuropathologic study. Neurology 29, 1209–1214.PubMedGoogle Scholar
  32. Hansen L., Salmon D., Galasko D., et al. (1990) The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology 40, 1–8.PubMedGoogle Scholar
  33. Hardy J. and Gwinn-Hardy K. (1998) Genetic classification of primary neurodegenerative disease. Science 282, 1075–1079.PubMedCrossRefGoogle Scholar
  34. Huntington’s Disease Collaborative Group. (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983.CrossRefGoogle Scholar
  35. Ingram E. M. and Spillantini M. G. (2002) Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends Mol. Med. 8, 555–562.PubMedCrossRefGoogle Scholar
  36. Irizarry M. C., Growdon W., Gomez-Isla T., et al. (1998) Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson’s disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. J. Neuropathol. Exp. Neurol. 57, 334–337.PubMedGoogle Scholar
  37. Ishizawa T., Mattila P., Davies P., Wang D., and Dickson, D. W. (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J. Neuropathol. Exp. Neurol. 62, 389–397.PubMedGoogle Scholar
  38. Iwai A., Masliah E., Yoshimoto M., et al. (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14, 467–475.PubMedCrossRefGoogle Scholar
  39. Jakes R., Spillantini M. G., and Goedert M. (1994) Identification of two distinct synucleins from human brain. FEBS Lett. 345, 27–32.PubMedCrossRefGoogle Scholar
  40. Kampers T., Friedhoff P., Biernat J., Mandelkow E. M., and Mandelkow E. (1996) RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 399, 344–349.PubMedCrossRefGoogle Scholar
  41. Katzman R., Galasko D., Saitoh T., Thal L. J., and Hansen L. (1995) Genetic evidence that the Lewy body variant is indeed a phenotypic variant of Alzheimer’s disease. Brain Cogn. 28, 259–265.PubMedCrossRefGoogle Scholar
  42. Kelenyi G. (1967) Thioflavin S fluorescent and Congo red anisotropic staining in the histologic demonstration of amyloid. Acta Neuropathol. (Berl.) 7, 336–348.CrossRefGoogle Scholar
  43. Klement I. A., Skinner P. J., Kaytor M. D., et al. (1998) Ataxin-1 nuclear localization and aggregation: role in polyglumatine-induced disease in SCA1 transgenic mice. Cell 95, 41–53.PubMedCrossRefGoogle Scholar
  44. Klunk W. E., Pettegrew J. W., and Abraham D. J. (1989) Quantitative evaluation of congo red binding to amyloid-like proteins with a beta-pleated sheet conformation. J. Histochem. Cytochem. 37, 1273–1281.PubMedGoogle Scholar
  45. Kobayashi K., Miyazu K., Katsukawa K., et al. (1992) Cytoskeletal protein abnormalities in patients with olivopontocerebellar atrophy—an immunocytochemical and Gallyas silver impregnation study. Neuropathol. Appl. Neurobiol. 18, 237–249.PubMedGoogle Scholar
  46. Kruger R., Kuhn W., Muller T., et al. (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat. Genet. 18, 106–108.PubMedCrossRefGoogle Scholar
  47. Ladewig P. (1945) Double-refringence of the amyloid-congo-red-complex in histological sections. Nature 156, 81–82.Google Scholar
  48. Lee V. M.-Y., Goedert M., and Trojanoswki, J. Q. (2001) Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159.PubMedCrossRefGoogle Scholar
  49. Lee V. M.-Y. and Trojanowski J. Q. (1999) Neurodegenerative tauopathies: human disease and transgenic mouse models. Neuron 24, 507–510.PubMedCrossRefGoogle Scholar
  50. Lewis J., Dickson D. W., Lin W.-L., et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1490.PubMedCrossRefGoogle Scholar
  51. Lewis J., McGowan E., Rockwood J., et al. (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402–405.PubMedCrossRefGoogle Scholar
  52. Lippa C. F., Fujiwara H., Mann D. M., et al. (1998) Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am. J. Pathol. 153, 1365–1370.PubMedGoogle Scholar
  53. Lippa C. F., Schmidt M. L., Lee V. M.-Y., and Trojanowski J. Q (1999) Antibodies to alpha-synuclein detect Lewy bodies in many Down’s syndrome brains with Alzheimer’s disease. Ann. Neurol. 45, 353–357.PubMedCrossRefGoogle Scholar
  54. Markopoulou K., Wszolek Z. K., Pfeiffer R.F., and Chase B. A. (1999) Reduced expression of the G209A alpha-synuclein allele in familial Parkinsonism. Ann. Neurol. 46, 374–381.PubMedCrossRefGoogle Scholar
  55. Marui W., Iseki E., Ueda K., and Kosaka K. (2000) Occurrence of human alpha-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer’s disease. J. Neurol. Sci. 174, 81–84.PubMedCrossRefGoogle Scholar
  56. Masliah E., Rockenstein E., Veinbergs I., et al. (2001) beta-Amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc. Natl. Acad. Sci. USA 98, 12245–12250.PubMedCrossRefGoogle Scholar
  57. Murayama S., Arima K., Nakazato Y., et al. (1992) Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. 2. Oligodendroglial cytoplasmic inclusions. Acta Neuropathol. (Berl.) 84, 32–38.CrossRefGoogle Scholar
  58. Murphy D. D., Rueter S. M., Trojanowski J. Q., and Lee V. M.-Y. (2000) Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J. Neurosci. 20, 3214–3220.PubMedGoogle Scholar
  59. Nacharaju P., Lewis J., Easson C., et al. (1999) Accelerated filament formation from tau protein with specific FTDP-17 missense. FEBS Lett. 447, 195–199.PubMedCrossRefGoogle Scholar
  60. Papadimitriou A., Veletza V., Hadjigeorgiou G. M., et al. (1999) Mutated alpha-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance? Neurology 52, 651–654.PubMedGoogle Scholar
  61. Papp M. I. and Lantos P. L. (1992) Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in multiple system atrophy. J. Neurol. Sci. 107, 172–182.PubMedCrossRefGoogle Scholar
  62. Perry R. H., Irving D., Blessed G., Fairbairn A., and Perry E. K. (1990) Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in the elderly. J. Neurol. Sci. 95, 119–139.PubMedCrossRefGoogle Scholar
  63. Piao Y. S., Hayashi S., Hasegawa M., et al. (2001) Co-localization of alpha-synuclein and phosphorylated tau in neuronal and glial cytoplasmic inclusions in a patient with multiple system atrophy of long duration. Acta Neuropathol. (Berl.) 101, 285–293.Google Scholar
  64. Polymeropoulos M. H., Lavedan C., Leroy E., et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047.PubMedCrossRefGoogle Scholar
  65. Probst-Cousin S., Bergmann M., Kuchelmeister K., Schroder R., and Schmid K. W. (1996) Ubiquitin-positive inclusions in different types of multiple system atrophy: distribution and specificity. Pathol. Res. Pract. 192, 453–461.PubMedGoogle Scholar
  66. Samuel W., Galasko D., Masliah E., and Hansen L. A. (1996) Neocortical lewy body counts correlate with dementia in the Lewy body variant of Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 55, 44–52.PubMedGoogle Scholar
  67. Saudou F., Finbeiner S., Devys D., and Greenberg M. E. (1998) Huningtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66.PubMedCrossRefGoogle Scholar
  68. Schmidt M. L., Martin J. A., Lee V. M.-Y., and Trojanowski J. Q. (1996) Convergence of Lewy bodies and neurofibrillary tangles in amygdala neurons of Alzheimer’s disease and Lewy body disorders. Acta Neuropathol. (Berl.) 91, 475–481.CrossRefGoogle Scholar
  69. Selkoe D. J. (2002) The origins of Alzheimer’s disease. JAMA 283, 1615–1617.CrossRefGoogle Scholar
  70. Serpell L. C. (2000) Alzheimer’s amyloid fibrils: structure and assembly. Biochim. Biophys. Acta 1502, 16–30.PubMedGoogle Scholar
  71. Serpell L. C., Berriman J., Jakes R., Goedert M., and Crowther R. A. (2000) Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. Proc. Natl. Acad. Sci. USA 97, 4897–4902.PubMedCrossRefGoogle Scholar
  72. Sipe J. D. and Cohen A. S. (2000) Review: history of the amyloid fibril. J. Struct. Biol. 130, 88–98.PubMedCrossRefGoogle Scholar
  73. Souza J. M., Giasson B. I., Lee V. M.-Y., and Ischiropoulos H (2000) Chaperone-like activity of synucleins. FEBS Lett. 474, 116–119.PubMedCrossRefGoogle Scholar
  74. Spillantini M. G., Crowther R. A., Jakes R., et al. (1998a) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 251, 205–208.PubMedCrossRefGoogle Scholar
  75. Spillantini M. G., Crowther R. A., Jakes R., Hasegawa M., and Goedert M. (1998b) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. USA 95, 6469–6473.PubMedCrossRefGoogle Scholar
  76. Spillantini M. G., Schmidt M. L., Lee V. M.-Y., et al. (1997) Alpha-synuclein in Lewy bodies. Nature 388, 839–840.PubMedCrossRefGoogle Scholar
  77. Spira P. J., Sharpe D. M., Halliday G., Cavanagh J., and Nicholson G. A. (2001) Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann. Neurol. 49, 313–319.PubMedCrossRefGoogle Scholar
  78. Takeda A., Arai N., Komori T., et al. (1997) Tau immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci. Lett. 234, 63–66.PubMedCrossRefGoogle Scholar
  79. Takeda A., Mallory M., Sundsmo M., et al (1998) Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am. J. Pathol. 152, 367–372.PubMedGoogle Scholar
  80. Taylor J. P., Hardy J., and Fischbeck, K. H. (2002) Toxic proteins in neurodegenerative disease. Science 296, 1991–1995.PubMedCrossRefGoogle Scholar
  81. Trojanowski J. Q., Goedert M., Iwatsubo T., et al. (1998) Fatal attractions: abnormal protein aggregation and neuron death in Parkinson’s disease and Lewy body dementia. Cell Death. Differ. 5, 832–837.PubMedCrossRefGoogle Scholar
  82. Trojanowski J. Q. and Lee V. M.-Y. (2000) “Fatal attractions” of proteins. A comprehensive hypothetical mechanism underlying Alzheimer’s disease and other neurodegenerative disorders. Ann. N. Y. Acad. Sci. 924, 62–67.PubMedCrossRefGoogle Scholar
  83. Tu P. H., Galvin J. E., Baba M., et al. (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann. Neurol. 44, 415–422.PubMedCrossRefGoogle Scholar
  84. Weinreb P. H., Zhen W., Poon A. W., Conway K. A., and Lansbury P. T. (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35, 13709–13715.PubMedCrossRefGoogle Scholar
  85. Wilson C. A., Doms R. W., and Lee, V. M.-Y. (1999) Intracellular APP processing and Aβ production in Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 58, 787–794.PubMedGoogle Scholar
  86. Withers G. S., George J. M., Banker G. A., and Clayton D. F. (1997) Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res. Dev. Brain Res. 99, 87–94.PubMedCrossRefGoogle Scholar
  87. Wood S. J., Wypych J., Steavenson S., et al. (1999) alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson’s disease. J. Biol. Chem. 274, 19509–19512.PubMedCrossRefGoogle Scholar
  88. Yamazaki M., Arai Y., Baba M., et al. (2000) Alpha-synuclein inclusions in amygdala in the brains of patients with the parkinsonism-dementia complex of Guam. J. Neuropathol. Exp. Neurol. 59, 585–591.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Benoit I. Giasson
    • 1
  • Virginia M. Y. Lee
    • 1
    • 2
  • John Q. Trojanowski
    • 1
    • 2
    Email author
  1. 1.Department of Pathology and Laboratory MedicineCenter for Neurodegenerative Disease ResearchPhiladelphia
  2. 2.Institute on Aging of the University of PennsylvaniaPhiladelphia

Personalised recommendations