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A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration

Abstract

There has been an explosion in the number of papers discussing the hypothesis of 'pathogenic spread' in neurodegenerative disease — the idea that abnormal forms of disease-associated proteins, such as tau or α-synuclein, physically move from neuron to neuron to induce disease progression. However, whether inter-neuronal spread of protein aggregates actually occurs in humans and, if so, whether it causes symptom onset remain uncertain. Even if pathogenic spread is proven in humans, it is unclear how much this would alter the specific therapeutic approaches that are in development. A critical appraisal of this increasingly popular hypothesis thus seems both important and timely.

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Figure 1: The pathogenic spread and selective vulnerability hypotheses.
Figure 2: Possible mechanisms for inter-neuronal transfer of proteins.
Figure 3: Strategies for targeting disease-associated neural protein aggregates.

References

  1. Selkoe, D. J. Folding proteins in fatal ways. Nature 426, 900–904 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Soto, C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4, 49–60 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).

    Article  CAS  PubMed  Google Scholar 

  4. Prusiner, S. B. Cell biology. A unifying role for prions in neurodegenerative diseases. Science 336, 1511–1513 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Frost, B. & Diamond, M. I. Prion-like mechanisms in neurodegenerative diseases. Nat. Rev. Neurosci. 11, 155–159 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Brettschneider, J., Del Tredici, K., Lee, V. M. & Trojanowski, J. Q. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat. Rev. Neurosci. 16, 109–120 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Glenner, G. G. Amyloid deposits and amyloidosis. The β-fibrilloses (first of two parts). N. Engl. J. Med. 302, 1283–1292 (1980).

    Article  CAS  PubMed  Google Scholar 

  8. Jarrett, J. T. & Lansbury, P. T. Jr. Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055–1058 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Walsh, D. M. & Selkoe, D. J. Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Protein Pept. Lett. 11, 213–228 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  11. Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H. & Del Tredici, K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112, 389–404 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Brundin, P., Melki, R. & Kopito, R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat. Rev. Mol. Cell Biol. 11, 301–307 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guest, W. C. et al. Generalization of the prion hypothesis to other neurodegenerative diseases: an imperfect fit. J. Toxicol. Environ. Health A 74, 1433–1459 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Aguzzi, A. Cell biology: beyond the prion principle. Nature 459, 924–925 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Ashe, K. H. & Aguzzi, A. Prions, prionoids and pathogenic proteins in Alzheimer disease. Prion 7, 55–59 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mattson, M. P. & Magnus, T. Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 7, 278–294 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jackson, W. S. Selective vulnerability to neurodegenerative disease: the curious case of prion protein. Dis. Model. Mech. 7, 21–29 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Petersen, R. B., Parchi, P., Richardson, S. L., Urig, C. B. & Gambetti, P. Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. J. Biol. Chem. 271, 12661–12668 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Gambetti, P., Kong, Q., Zou, W., Parchi, P. & Chen, S. G. Sporadic and familial CJD: classification and characterisation. Br. Med. Bull. 66, 213–239 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Kimberlin, R. H., Hall, S. M. & Walker, C. A. Pathogenesis of mouse scrapie. Evidence for direct neural spread of infection to the CNS after injection of sciatic nerve. J. Neurol. Sci. 61, 315–325 (1983).

    Article  CAS  PubMed  Google Scholar 

  21. Scott, J. R. & Fraser, H. Transport and targeting of scrapie infectivity and pathology in the optic nerve projections following intraocular infection. Prog. Clin. Biol. Res. 317, 645–652 (1989).

    CAS  PubMed  Google Scholar 

  22. Yoshiyama, Y., Lee, V. M. & Trojanowski, J. Q. Frontotemporal dementia and tauopathy. Curr. Neurol. Neurosci. Rep. 1, 413–421 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Hansen, L. A., Masliah, E., Galasko, D. & Terry, R. D. Plaque-only Alzheimer disease is usually the Lewy body variant, and vice versa. J. Neuropathol. Exp. Neurol. 52, 648–654 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Avila, J., Lucas, J. J., Perez, M. & Hernandez, F. Role of tau protein in both physiological and pathological conditions. Physiol. Rev. 84, 361–384 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Braak, H. & Del Tredici, K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 121, 171–181 (2011).

    Article  PubMed  Google Scholar 

  27. Jellinger, K. A. A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol. 116, 1–16 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Beach, T. G. et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 117, 613–634 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Farrer, M. et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann. Neurol. 50, 293–300 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Takahashi, H. et al. Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 44, 437–441 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. van de Warrenburg, B. P. et al. Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 56, 555–557 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat. Med. 14, 504–506 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Brundin, P. & Kordower, J. H. Neuropathology in transplants in Parkinson's disease: implications for disease pathogenesis and the future of cell therapy. Prog. Brain Res. 200, 221–241 (2012).

    Article  PubMed  Google Scholar 

  34. Ahn, T. B., Langston, J. W., Aachi, V. R. & Dickson, D. W. Relationship of neighboring tissue and gliosis to α-synuclein pathology in a fetal transplant for Parkinson's disease. Am. J. Neurodegener. Dis. 1, 49–59 (2012).

    PubMed  PubMed Central  Google Scholar 

  35. Cooper, O. et al. Lack of functional relevance of isolated cell damage in transplants of Parkinson's disease patients. J. Neurol. 256 (Suppl. 3), 310–316 (2009).

    Article  PubMed  Google Scholar 

  36. Hallett, P. J. et al. Long-term health of dopaminergic neuron transplants in Parkinson's disease patients. Cell Rep. 7, 1755–1761 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Barker, R. A., Barrett, J., Mason, S. L. & Björklund, A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease. Lancet Neurol. 12, 84–91 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685–697 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7, e31302 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yetman, M. J., Lillehaug, S., Bjaalie, J. G., Leergaard, T. B. & Jankowsky, J. L. Transgene expression in the Nop-tTA driver line is not inherently restricted to the entorhinal cortex. Brain Struct. Funct. http://dx.doi.org/10.1007/s00429-015-1040-9 (2015).

  41. Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl Acad. Sci. USA 110, 9535–9540 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Stancu, I. C. et al. Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta Neuropathol. 129, 875–894 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ridley, R. M., Baker, H. F., Windle, C. P. & Cummings, R. M. Very long term studies of the seeding of beta-amyloidosis in primates. J. Neural Transm. 113, 1243–1251 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Recasens, A. et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol. 75, 351–362 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Terry, R. D. Do neuronal inclusions kill the cell? J. Neural Transm. Suppl. 59, 91–93 (2000).

    CAS  PubMed  Google Scholar 

  49. Caughey, B. & Lansbury, P. T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Berger, Z. et al. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J. Neurosci. 27, 3650–3662 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wegmann, S. et al. Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity. EMBO J. 34, 3028–3041 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Benilova, I., Karran, E. & De Strooper, B. The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes. Nat. Neurosci. 15, 349–357 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Blennow, K. et al. Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol. Chem. Neuropathol. 26, 231–245 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Motter, R. et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann. Neurol. 38, 643–648 (1995).

    Article  CAS  PubMed  Google Scholar 

  56. Hawkes, C. H., Del Tredici, K. & Braak, H. Parkinson's disease: the dual hit theory revisited. Ann. NY Acad. Sci. 1170, 615–622 (2009).

    Article  PubMed  Google Scholar 

  57. Barten, D. M. et al. Tau transgenic mice as models for cerebrospinal fluid tau biomarkers. J. Alzheimers Dis. 24 (Suppl. 2), 127–141 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Chai, X., Dage, J. L. & Citron, M. Constitutive secretion of tau protein by an unconventional mechanism. Neurobiol. Dis. 48, 356–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Mably, A. J. et al. Tau immunization: a cautionary tale? Neurobiol. Aging 36, 1316–1332 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Zetterberg, H. et al. Plasma tau levels in Alzheimer's disease. Alzheimers Res. Ther. 5, 9 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Borghi, R. et al. Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects. Neurosci. Lett. 287, 65–67 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. El-Agnaf, O. M. et al. α-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 17, 1945–1947 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Mollenhauer, B. et al. α-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol. 10, 230–240 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Masliah, E. et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS ONE 6, e19338 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J. Neurosci. 30, 16559–16566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Holmes, B. B. et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl Acad. Sci. USA 110, E3138–E3147 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Caughey, B. & Baron, G. S. Prions and their partners in crime. Nature 443, 803–810 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Borchelt, D. R., Rogers, M., Stahl, N., Telling, G. & Prusiner, S. B. Release of the cellular prion protein from cultured cells after loss of its glycoinositol phospholipid anchor. Glycobiology 3, 319–329 (1993).

    Article  CAS  PubMed  Google Scholar 

  69. Harris, D. A. et al. Processing of a cellular prion protein: identification of N- and C-terminal cleavage sites. Biochemistry 32, 1009–1016 (1993).

    Article  CAS  PubMed  Google Scholar 

  70. Altmeppen, H. C. et al. Proteolytic processing of the prion protein in health and disease. Am. J. Neurodegener Dis. 1, 15–31 (2012).

    PubMed  PubMed Central  Google Scholar 

  71. Halliday, M., Radford, H. & Mallucci, G. R. Prions: generation and spread versus neurotoxicity. J. Biol. Chem. 289, 19862–19868 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sandberg, M. K. et al. Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked. Nat. Commun. 5, 4347 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chiesa, R. & Harris, D. A. Prion diseases: what is the neurotoxic molecule? Neurobiol. Dis. 8, 743–763 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Solomon, I. H., Schepker, J. A. & Harris, D. A. Prion neurotoxicity: insights from prion protein mutants. Curr. Issues Mol. Biol. 12, 51–61 (2010).

    CAS  PubMed  Google Scholar 

  75. Collinge, J. & Clarke, A. R. A general model of prion strains and their pathogenicity. Science 318, 930–936 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Holmqvist, S. et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805–820 (2014).

    Article  PubMed  Google Scholar 

  77. Wakabayashi, K., Takahashi, H., Ohama, E. & Ikuta, F. Parkinson's disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol. 79, 581–583 (1990).

    Article  CAS  PubMed  Google Scholar 

  78. Hawkes, C. H., Shephard, B. C. & Daniel, S. E. Is Parkinson's disease a primary olfactory disorder? QJM 92, 473–480 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Wang, N., Gibbons, C. H., Lafo, J. & Freeman, R. α-Synuclein in cutaneous autonomic nerves. Neurology 81, 1604–1610 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lemere, C. A. et al. Sequence of deposition of heterogeneous amyloid β-peptides and Apo E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3, 16–32 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Frost, B., Ollesch, J., Wille, H. & Diamond, M. I. Conformational diversity of wild-type Tau fibrils specified by templated conformation change. J. Biol. Chem. 284, 3546–3551 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Watts, J. C. et al. Transmission of multiple system atrophy prions to transgenic mice. Proc. Natl Acad. Sci. USA 110, 19555–19560 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Guo, J. L. & Lee, V. M. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat. Med. 20, 130–138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mirbaha, H., Holmes, B. B., Sanders, D. W., Bieschke, J. & Diamond, M. I. Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation. J. Biol. Chem. 290, 14893–14903 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Usenovic, M. et al. Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J. Neurosci. 35, 14234–14250 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Brown, P. et al. Iatrogenic Creutzfeldt–Jakob disease at the millennium. Neurology 55, 1075–1081 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Wroe, S. J. et al. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt–Jakob disease associated with blood transfusion: a case report. Lancet 368, 2061–2067 (2006).

    Article  PubMed  Google Scholar 

  89. Collinge, J. Variant Creutzfeldt–Jakob disease. Lancet 354, 317–323 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. Will, R. G. et al. A new variant of Creutzfeldt–Jakob disease in the UK. Lancet 347, 921–925 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Beekes, M., Thomzig, A., Schulz-Schaeffer, W. J. & Burger, R. Is there a risk of prion-like disease transmission by Alzheimer- or Parkinson-associated protein particles? Acta Neuropathol. 128, 463–476 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Irwin, D. J. et al. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 70, 462–468 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Goudsmit, J. et al. Evidence for and against the transmissibility of Alzheimer disease. Neurology 30, 945–950 (1980).

    Article  CAS  PubMed  Google Scholar 

  94. Godec, M. S. et al. Evidence against the transmissibility of Alzheimer's disease. Neurology 41, 1320 (1991).

    Article  CAS  PubMed  Google Scholar 

  95. Brown, P. et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann. Neurol. 35, 513–529 (1994).

    Article  CAS  PubMed  Google Scholar 

  96. Baker, H. F., Ridley, R. M., Duchen, L. W., Crow, T. J. & Bruton, C. J. Induction of beta (A4)-amyloid in primates by injection of Alzheimer's disease brain homogenate. Comparison with transmission of spongiform encephalopathy. Mol. Neurobiol. 8, 25–39 (1994).

    Article  CAS  PubMed  Google Scholar 

  97. Baker, H. F., Ridley, R. M., Duchen, L. W., Crow, T. J. & Bruton, C. J. Evidence for the experimental transmission of cerebral beta-amyloidosis to primates. Int. J. Exp. Pathol. 74, 441–454 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Rewcastle, N., Gibbs, C. J. & Gajdusek, D. Transmission of familial Alzheimer's disease to primates. J. Neuropathol. Exp. Neurol. 37, 679 (1978).

    Article  Google Scholar 

  99. Viola, K. L. et al. Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease. Nat. Nanotechnol. 10, 91–98 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Moreno, J. A. et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med. 5, 206ra138 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Greig, J. R. Scrapie: observations on the transmission of the disease by mediate contact. Veterinary J. 96, 203–206 (1940).

    Google Scholar 

  102. Cuille, J. & Chelle, P. L. Investigations of scrapie in sheep. Veterinary Med. 34, 417 (1939).

    Google Scholar 

  103. Chandler, R. L. Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet 1, 1378–1379 (1961).

    Article  CAS  PubMed  Google Scholar 

  104. Hadlow, W. J. Scrapie and kuru. Lancet 274, 289–290 (1959).

    Article  Google Scholar 

  105. Gajdusek, D. C., Gibbs, C. J. & Alpers, M. Experimental transmission of a Kuru-like syndrome to chimpanzees. Nature 209, 794–796 (1966).

    Article  CAS  PubMed  Google Scholar 

  106. Klatzo, I., Gajdusek, D. C. & Zigas, V. Pathology of Kuru. Lab. Invest. 8, 799–847 (1959).

    CAS  PubMed  Google Scholar 

  107. Gibbs, C. J. Jr et al. Creutzfeldt–Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science 161, 388–389 (1968).

    Article  PubMed  Google Scholar 

  108. Griffith, J. S. Self-replication and scrapie. Nature 215, 1043–1044 (1967).

    Article  CAS  PubMed  Google Scholar 

  109. Bolton, D. C., McKinley, M. P. & Prusiner, S. B. Identification of a protein that purifies with the scrapie prion. Science 218, 1309–1311 (1982).

    Article  CAS  PubMed  Google Scholar 

  110. Oesch, B. et al. A cellular gene encodes scrapie PrP 27–30 protein. Cell 40, 735–746 (1985).

    Article  CAS  PubMed  Google Scholar 

  111. Chesebro, B. et al. Identification of scrapie prion protein-specific mRNA in scrapie-infected and uninfected brain. Nature 315, 331–333 (1985).

    Article  CAS  PubMed  Google Scholar 

  112. Hsiao, K. K. et al. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 250, 1587–1590 (1990).

    Article  CAS  PubMed  Google Scholar 

  113. Lloyd, S. E., Mead, S. & Collinge, J. Genetics of prion diseases. Curr. Opin. Genet. Dev. 23, 345–351 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bueler, H. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993).

    Article  CAS  PubMed  Google Scholar 

  115. Come, J. H., Fraser, P. E. & Lansbury, P. T. Jr. A kinetic model for amyloid formation in the prion diseases: importance of seeding. Proc. Natl Acad. Sci. USA 90, 5959–5963 (1993).

    Article  CAS  PubMed  Google Scholar 

  116. Eigen, M. Prionics or the kinetic basis of prion diseases. Biophys. Chem. 63, A1–A18 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. Cohen, S. I. et al. Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc. Natl Acad. Sci. USA 110, 9758–9763 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Silveira, J. R. et al. The most infectious prion protein particles. Nature 437, 257–261 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Safar, J. et al. Eight prion strains have PrP(Sc) molecules with different conformations. Nat. Med. 4, 1157–1165 (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Cronier, S. et al. Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin. Biochem. J. 416, 297–305 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sandberg, M. K., Al-Doujaily, H., Sharps, B., Clarke, A. R. & Collinge, J. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 470, 540–542 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Kane, M. D. et al. Evidence for seeding of β-amyloid by intracerebral infusion of Alzheimer brain extracts in β-amyloid precursor protein-transgenic mice. J. Neurosci. 20, 3606–3611 (2000).

    Article  CAS  PubMed  Google Scholar 

  123. Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Rosen, R. F. et al. Exogenous seeding of cerebral β-amyloid deposition in βAPP-transgenic rats. J. Neurochem. 120, 660–666 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Stohr, J. et al. Purified and synthetic Alzheimer's amyloid beta (Aβ) prions. Proc. Natl Acad. Sci. USA 109, 11025–11030 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Harper, J. D. & Lansbury, P. T. Jr. 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, 385–407 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Arosio, P., Knowles, T. P. & Linse, S. On the lag phase in amyloid fibril formation. Phys. Chem. Chem. Phys. 17, 7606–7618 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Esparza, T. J. et al. Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann. Neurol. 73, 104–119 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Cummings, C. J. et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24, 879–892 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. & Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Serrano-Pozo, A. et al. Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology. Brain 133, 1312–1327 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Koffie, R. M. et al. Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc. Natl Acad. Sci. USA 106, 4012–4017 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Langer, F. et al. Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J. Neurosci. 31, 14488–14495 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Eisele, Y. S. et al. Peripherally applied Aβ-containing inoculates induce cerebral β-amyloidosis. Science 330, 980–982 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jaunmuktane, Z. et al. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525, 247–250 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Jaunmuktane, Z. et al. Erratum: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 526, 595 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Thery, C. et al. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J. Immunol. 166, 7309–7318 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H. H. Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004).

    Article  CAS  PubMed  Google Scholar 

  140. Caughey, B., Baron, G. S., Chesebro, B. & Jeffrey, M. Getting a grip on prions: oligomers, amyloids, and pathological membrane interactions. Annu. Rev. Biochem. 78, 177–204 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hashimoto, M. & Masliah, E. Alpha-synuclein in Lewy body disease and Alzheimer's disease. Brain Pathol. 9, 707–720 (1999).

    Article  CAS  PubMed  Google Scholar 

  142. Ittner, L. M. et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 142, 387–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Zempel, H. et al. Amyloid-β oligomers induce synaptic damage via tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 32, 2920–2937 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kanmert, D. et al. C-terminally truncated forms of tau, but not full-length tau or its C-terminal fragments, are released from neurons independently of cell death. J. Neurosci. 35, 10851–10865 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Cho, Y. et al. Personalized medicine approach for optimizing the dose of tafamidis to potentially ameliorate wild-type transthyretin amyloidosis (cardiomyopathy). Amyloid 22, 175–180 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Dettmer, U. et al. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 6, 7314 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Bartels, T., Choi, J. G. & Selkoe, D. J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107–110 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank C. Masters, R. Ridley and S. Bradner for sharing unpublished results, and S. Brandner, P. Brundin, B. Caughey, J. Collinge, D. Harris, O. Isacson, J. Kordower, V. O'Connor and H. Perry for discussions. This work was support by grants from the US National Institutes of Health to D.M.W. (AG046275 and AG047505) and D.J.S. (AG06173 and NS083845).

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Walsh, D., Selkoe, D. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci 17, 251–260 (2016). https://doi.org/10.1038/nrn.2016.13

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