Advertisement

The Prion-Like Aspect of Alzheimer Pathology

  • Sarah K. Fritschi
  • Bahareh Eftekharzadeh
  • Giusi Manfredi
  • Tsuyoshi Hamaguchi
  • Götz Heilbronner
  • Amudha Nagarathinam
  • Franziska Langer
  • Yvonne S. Eisele
  • Lary Walker
  • Mathias JuckerEmail author
Chapter
Part of the Research and Perspectives in Alzheimer's Disease book series (ALZHEIMER)

Abstract

Many neurodegenerative disorders are characterized by a predictable spatiotemporal progression of the aggregation of specific proteins in the brain. The most prevalent cerebral proteopathy is Alzheimer’s disease (AD), in which aggregated amyloid-β peptide (Aβ) is deposited in the form of extracellular parenchymal plaques and vascular amyloid. Multiple lines of evidence indicate that β-amyloidosis can be exogenously induced by the application of brain extracts containing aggregated Aβ. The β-amyloid-inducing agent in the extract is likely Aβ itself in a conformation that cannot easily be mimicked with synthetic material. The induced Aβ lesions spread over time within and among brain regions, and they are dependent on the structural and biochemical nature of Aβ in the extract and on the characteristics of the host. We have found that bioactive Aβ seeds exist in both soluble and insoluble forms; some of them are sensitive to proteinase-K digestion and some are not. Observations of similar prion-like induction, spreading, and transmission of tau lesions, the second hallmark of AD pathology, and more recent observations of seeded α-synuclein lesions suggest that the concept of prion-like corruptive templating of proteins may also apply to intracellular lesions in neurodegenerative diseases. The clinical implications of these observations are not yet clear. The finding that the Aβ seeds are partly soluble suggests that such seeds in bodily fluids may have diagnostic value and also that they could represent a novel target for early therapeutic intervention. Furthermore, the possibility that mechanisms exist allowing for the transport of Aβ aggregates (and possibly other seeds) from the periphery to the brain raises the speculation that environmental amyloidogenic seeds might act as risk factors for certain neurodegenerative diseases.

Keywords

Prion Disease Alzheimer Pathology Brain Extract Intracerebral Inoculation Intracerebral Infusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ (1993) Evidence for the experimental transmission of cerebral beta-amyloidosis to primates. Int J Exp Pathol 74:441–454PubMedGoogle Scholar
  2. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  3. Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181PubMedCrossRefGoogle Scholar
  4. Brown P, Salazar AM, Gibbs CJ, Gajdusek DC (1982) Alzheimer’s disease and transmissible virus dementia (Creutzfeldt-Jakob disease). Ann NY Acad Sci 396:131–143PubMedCrossRefGoogle Scholar
  5. Brundin P, Melki R, Kopito R (2010) Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 11:301–307PubMedCrossRefGoogle Scholar
  6. Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 225:7709–7717CrossRefGoogle Scholar
  7. Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Calson GA, Spires-Jones TL, Hyman BT (2012) Propagation of Tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697PubMedCrossRefGoogle Scholar
  8. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913PubMedCrossRefGoogle Scholar
  9. Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M (2009) Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci USA 106:12926–12931PubMedCrossRefGoogle Scholar
  10. Eisele YS, Obermüller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, Walker LC, Staufenbiel M, Heikenwalder M, Jucker M (2010) Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 330:980–982PubMedCrossRefGoogle Scholar
  11. Eisenberg D, Jucker M (2012) The amyloid state of proteins in human diseases. Cell 148: 1188–1203PubMedCrossRefGoogle Scholar
  12. Frost B, Diamond MI (2010) Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 11:155–159PubMedGoogle Scholar
  13. Frost B, Jacks RL, Diamond MI (2009a) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852PubMedCrossRefGoogle Scholar
  14. Frost B, Ollesch J, Wille H, Diamond MI (2009b) Conformational diversity of wild-type Tau fibrils specified by templated conformation change. J Biol Chem 284:3546–3551PubMedCrossRefGoogle Scholar
  15. Godec MS, Asher DM, Masters CL, Kozachuk WE, Friedland RP, Gibbs CJ Jr, Gajdusek DC, Rapoport SI, Schapiro MB (1991) Evidence against the transmissibility of Alzheimer’s disease. Neurology 41:1320PubMedCrossRefGoogle Scholar
  16. Goedert M, Clavaguera F, Tolnay M (2010) The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 33:317–325PubMedCrossRefGoogle Scholar
  17. Golde TE, Schneider LS, Koo EH (2011) Anti-aβ therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron 69:203–213PubMedCrossRefGoogle Scholar
  18. Goudsmit J, Morrow CH, Asher DM, Yanagihara RT, Masters CL, Gibbs CJ Jr, Gajdusek DC (1980) Evidence for and against the transmissibility of Alzheimer disease. Neurology 30: 945–950PubMedCrossRefGoogle Scholar
  19. Guo JL, Lee VM-Y (2011) Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286:15317–15331PubMedCrossRefGoogle Scholar
  20. Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC, Jucker M (2012) The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol 123:31–37PubMedCrossRefGoogle Scholar
  21. Hansen C, Angot E, Bergström AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P (2011) α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 18:1–11Google Scholar
  22. Harper JD, Lansbury PT (1997) Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem 66:385–407PubMedCrossRefGoogle Scholar
  23. Holtzman DM, Morris JC, Goate AM (2011) Alzheimer’s disease: the challenge of the second century. Sci Transl Med 3:77sr1, ReviewPubMedCrossRefGoogle Scholar
  24. Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70:532–540Google Scholar
  25. Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA, Schwarz RD, Roher AE, Walker LC (2000) Evidence for seeding of beta-amyloid by intracerebral infusion of Alzheimer brain extracts in beta-amyloid precursor protein-transgenic mice. J Neurosci 20:3606–3611PubMedGoogle Scholar
  26. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 14:504–506PubMedCrossRefGoogle Scholar
  27. Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC, Jucker M (2011) Soluble A{beta} seeds are potent inducers of cerebral {beta}-amyloid deposition. J Neurosci 31:14488–14495PubMedCrossRefGoogle Scholar
  28. Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, DeArmond SJ, Prusiner SB (2004) Synthetic mammalian prions. Science 305:673–676PubMedCrossRefGoogle Scholar
  29. Levine H 3rd, Walker LC (2010) Molecular polymorphism of Abeta in Alzheimer’s disease. Neurobiol Aging 31:542–548PubMedCrossRefGoogle Scholar
  30. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503PubMedCrossRefGoogle Scholar
  31. Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7:e31302PubMedCrossRefGoogle Scholar
  32. Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VM-Y (2012a) Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 209(5):975–986PubMedCrossRefGoogle Scholar
  33. Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012b) Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109):949–953PubMedCrossRefGoogle Scholar
  34. Manuelidis EE, de Figueiredo JM, Kim JH, Fritch WW, Manuelidis L (1988) Transmission studies from blood of Alzheimer disease patients and healthy relatives. Proc Natl Acad Sci USA 85: 4898–4901PubMedCrossRefGoogle Scholar
  35. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784PubMedCrossRefGoogle Scholar
  36. Morales R, Duran-Aniotz C, Castilla J, Estrada LD, Soto C (2012) De novo induction of amyloid-β deposition in vivo. Mol Psychiatry 17:1347–1353PubMedCrossRefGoogle Scholar
  37. Mougenot AL, Nicot S, Bencsik A, Morignat E, Verchere J, Lakhdar L, Legastelois S, Baron T (2012) Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 33:2225–2228PubMedCrossRefGoogle Scholar
  38. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R (2005) Self-propagating, molecular-level polymorphism in Alzheimer’s beta-amyloid fibrils. Science 307:262–265PubMedCrossRefGoogle Scholar
  39. Prusiner SB (1984) Some speculations about prions, amyloid, and Alzheimer’s disease. N Engl J Med 310:661–663PubMedCrossRefGoogle Scholar
  40. Ridley RM, Baker HF, Windle CP, Cummings RM (2006) Very long term studies of the seeding of beta-amyloidosis in primates. J Neural Transm 113:1243–1251PubMedCrossRefGoogle Scholar
  41. Selkoe DJ (2011) Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med 17: 1060–1065PubMedCrossRefGoogle Scholar
  42. Soto C, Estrada L, Castilla J (2006) Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends Biochem Sci 31:150–155PubMedCrossRefGoogle Scholar
  43. Stöhr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, DeArmond SJ, Prusiner SB, Giles K (2012) Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions. Proc Natl Acad Sci USA 109(27):11025–11030PubMedCrossRefGoogle Scholar
  44. Thal DR, Capetillo-Zarate E, Del Tredici K, Braak H (2006) The development of amyloid beta protein deposits in the aged brain. Sci Aging Knowledge Environ 2006:re1PubMedCrossRefGoogle Scholar
  45. Walker LC, Jucker M (2011) Amyloid by default. Nat Neurosci 14:669–670PubMedCrossRefGoogle Scholar
  46. Walker LC, Callahan MJ, Bian F, Durham RA, Roher AE, Lipinski WJ (2002) Exogenous induction of cerebral beta-amyloidosis in betaAPP-transgenic mice. Peptides 23:1241–1247PubMedCrossRefGoogle Scholar
  47. Walker LC, Levine H, Mattson MP, Jucker M (2006a) Inducible proteopathies. Trends Neurosci 29:438–443PubMedCrossRefGoogle Scholar
  48. Walker L, Levine H, Jucker M (2006b) Koch’s postulate and infectious proteins. Acta Neuropathol 112:1–4PubMedCrossRefGoogle Scholar
  49. Wang F, Wang X, Yuan C-G, Ma J (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327:1132–1135PubMedCrossRefGoogle Scholar
  50. Watts JC, Giles K, Grillo SK, Lemus A, DeArmond SJ, Prusiner SB (2011) Bioluminescence imaging of Abeta deposition in bigenic mouse models of Alzheimer’s disease. Proc Natl Acad Sci USA 108:2528–2533PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Sarah K. Fritschi
    • 1
    • 2
  • Bahareh Eftekharzadeh
    • 1
    • 2
  • Giusi Manfredi
    • 1
    • 2
  • Tsuyoshi Hamaguchi
    • 1
    • 2
  • Götz Heilbronner
    • 1
    • 2
  • Amudha Nagarathinam
    • 1
    • 2
  • Franziska Langer
    • 1
    • 2
  • Yvonne S. Eisele
    • 1
    • 2
  • Lary Walker
    • 3
    • 4
  • Mathias Jucker
    • 1
    • 2
    Email author
  1. 1.Department of Cellular Neurology, Hertie Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
  2. 2.DZNE, German Center for Neurodegenerative DiseasesTübingenGermany
  3. 3.Yerkes National Primate Research CenterEmory UniversityAtlantaUSA
  4. 4.Department of NeurologyEmory UniversityAtlantaUSA

Personalised recommendations