Protein transmission in neurodegenerative disease

Abstract

Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as ‘pathological seeds’. Recent studies have made exciting progress in identifying the characteristics of different pathological seeds, particularly those isolated from diseased brains. Advances have also been made in our understanding of the molecular mechanisms that regulate the transmission process, and the influence of the host cell on the conformation and properties of pathological seeds. The aim of this Review is to summarize our current knowledge of the cell-to-cell transmission of pathological proteins and to identify key questions for future investigation.

Key points

  • Cell-to-cell transmission and the subsequent amplification of pathological proteins is emerging as a common mechanism for the progression of various neurodegenerative diseases.

  • Transmission within the CNS as well as from the peripheral nervous system to the CNS has been reported for multiple pathological proteins.

  • Multiple molecular mechanisms involved in the secretion, uptake and transport of pathological seeds have been identified.

  • Neurodegenerative disease-related pathological proteins are conformationally diverse.

  • Various factors can modulate the transmission process, including neuronal activity, glial cells, genetic risk factors and interactions with other pathological proteins.

  • Antibodies against pathological seeds, which are designed to block the transmission process, are currently in clinical trials.

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Fig. 1: Mechanisms for the transmission of pathological proteins between cells.
Fig. 2: Generation of different pathological protein strains.

References

  1. 1.

    Glenner, G. G. & Wong, C. W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).

  2. 2.

    Kosik, K. S., Joachim, C. L. & Selkoe, D. J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl Acad. Sci. USA 83, 4044–4048 (1986).

  3. 3.

    Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. & Goedert, M. -Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc. Natl Acad. Sci. USA 95, 6469–6473 (1998).

  4. 4.

    Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

  5. 5.

    DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

  6. 6.

    Clavaguera, F. et al. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 127, 299–301 (2014).

  7. 7.

    Luna, E. et al. Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity. Acta Neuropathol. 135, 855–875 (2018).

  8. 8.

    Aoyagi, A. et al. Aβ and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain. Sci. Transl. Med. 11, eaat8462 (2019).

  9. 9.

    Laferriere, F. et al. TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates. Nat. Neurosci. 22, 65–77 (2019).

  10. 10.

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

  11. 11.

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

  12. 12.

    Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101–113 (2017).

  13. 13.

    Guo, J. L. & Lee, V. M. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J. Biol. Chem. 286, 15317–15331 (2011).

  14. 14.

    Guo, J. L. et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J. Exp. Med. 213, 2635–2654 (2016).

  15. 15.

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

  16. 16.

    Volpicelli-Daley, L. A. et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011).

  17. 17.

    Braak, H. & Del Tredici, K. Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv. Anat. Embryol. Cell Biol. 201, 1–119 (2009).

  18. 18.

    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).

  19. 19.

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

  20. 20.

    Thal, D. R., Rub, U., Orantes, M. & Braak, H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002).

  21. 21.

    Thal, D. R. et al. Sequence of Aβ-protein deposition in the human medial temporal lobe. J. Neuropathol. Exp. Neurol. 59, 733–748 (2000).

  22. 22.

    Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

  23. 23.

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

  24. 24.

    Scholl, M. et al. PET imaging of tau deposition in the aging human brain. Neuron 89, 971–982 (2016).

  25. 25.

    Schwarz, A. J. et al. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain 139, 1539–1550 (2016).

  26. 26.

    Furman, J. L. et al. Widespread tau seeding activity at early Braak stages. Acta Neuropathol. 133, 91–100 (2017).

  27. 27.

    Kaufman, S. K., Del Tredici, K., Thomas, T. L., Braak, H. & Diamond, M. I. Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART. Acta Neuropathol. 136, 57–67 (2018).

  28. 28.

    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).

  29. 29.

    Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008).

  30. 30.

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

  31. 31.

    Cali, I. et al. Iatrogenic Creutzfeldt-Jakob disease with amyloid-β pathology: an international study. Acta Neuropathol. Commun. 6, 5 (2018).

  32. 32.

    Frontzek, K., Lutz, M. I., Aguzzi, A., Kovacs, G. G. & Budka, H. Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med. Wkly. 146, w14287 (2016).

  33. 33.

    Hamaguchi, T. et al. Significant association of cadaveric dura mater grafting with subpial Aβ deposition and meningeal amyloid angiopathy. Acta Neuropathol. 132, 313–315 (2016).

  34. 34.

    Herve, D. et al. Fatal Aβ cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years. Acta Neuropathol. 135, 801–803 (2018).

  35. 35.

    Ritchie, D. L. et al. Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol. 134, 221–240 (2017).

  36. 36.

    Duyckaerts, C. et al. Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Aβ pathology. Acta Neuropathol. 135, 201–212 (2018).

  37. 37.

    Luk, K. C. et al. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J. Exp. Med. 209, 975–986 (2012).

  38. 38.

    Mougenot, A. L. et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33, 2225–2228 (2012).

  39. 39.

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

  40. 40.

    Masuda-Suzukake, M. et al. Prion-like spreading of pathological α-synuclein in brain. Brain 136, 1128–1138 (2013).

  41. 41.

    Peng, C. et al. Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature 557, 558–563 (2018).

  42. 42.

    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).

  43. 43.

    Shimozawa, A. et al. Propagation of pathological α-synuclein in marmoset brain. Acta Neuropathol. Commun. 5, 12 (2017).

  44. 44.

    Ulusoy, A. et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol. Med. 5, 1119–1127 (2013).

  45. 45.

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

  46. 46.

    Peeraer, E. et al. Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice. Neurobiol. Dis. 73, 83–95 (2015).

  47. 47.

    Narasimhan, S. et al. Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. J. Neurosci. 37, 11406–11423 (2017).

  48. 48.

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

  49. 49.

    Lasagna-Reeves, C. A. et al. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci. Rep. 2, 700 (2012).

  50. 50.

    Zhang, W. et al. Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases. Elife 8, e43584 (2019).

  51. 51.

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

  52. 52.

    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. 221, 2231–2249 (2016).

  53. 53.

    Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

  54. 54.

    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).

  55. 55.

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

  56. 56.

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

  57. 57.

    Munch, C., O’Brien, J. & Bertolotti, A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc. Natl Acad. Sci. USA 108, 3548–3553 (2011).

  58. 58.

    Nekooki-Machida, Y. et al. Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proc. Natl Acad. Sci. USA 106, 9679–9684 (2009).

  59. 59.

    Ren, P. H. et al. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat. Cell Biol. 11, 219–225 (2009).

  60. 60.

    Chen, A. K. et al. Induction of amyloid fibrils by the C-terminal fragments of TDP-43 in amyotrophic lateral sclerosis. J. Am. Chem. Soc. 132, 1186–1187 (2010).

  61. 61.

    Nonaka, T. et al. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4, 124–134 (2013).

  62. 62.

    Porta, S. et al. Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat. Commun. 9, 4220 (2018).

  63. 63.

    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).

  64. 64.

    Wakabayashi, K., Takahashi, H., Takeda, S., Ohama, E. & Ikuta, F. Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses. Acta Neuropathol. 76, 217–221 (1988).

  65. 65.

    Killinger, B. A. et al. The vermiform appendix impacts the risk of developing Parkinson’s disease. Sci. Transl. Med. 10, eaar5280 (2018).

  66. 66.

    Del Tredici, K., Hawkes, C. H., Ghebremedhin, E. & Braak, H. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol. 119, 703–713 (2010).

  67. 67.

    Svensson, E. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).

  68. 68.

    Breid, S. et al. Neuroinvasion of α-synuclein prionoids after intraperitoneal and intraglossal inoculation. J. Virol. 90, 9182–9193 (2016).

  69. 69.

    Sacino, A. N. et al. Intramuscular injection of alpha-synuclein induces CNS alpha-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc. Natl Acad. Sci. USA 111, 10732–10737 (2014).

  70. 70.

    Ayers, J. I. et al. Robust central nervous system pathology in transgenic mice following peripheral injection of α-synuclein fibrils. J. Virol. 91, e02095-16 (2017).

  71. 71.

    Uemura, N. et al. Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Mol. Neurodegener. 13, 21 (2018).

  72. 72.

    Li, Q. X. et al. Proteolytic processing of Alzheimer’s disease beta A4 amyloid precursor protein in human platelets. J. Biol. Chem. 270, 14140–14147 (1995).

  73. 73.

    Evin, G., Zhu, A., Holsinger, R. M., Masters, C. L. & Li, Q. X. Proteolytic processing of the Alzheimer’s disease amyloid precursor protein in brain and platelets. J. Neurosci. Res. 74, 386–392 (2003).

  74. 74.

    Citron, M. et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc. Natl Acad. Sci. USA 91, 11993–11997 (1994).

  75. 75.

    Kuo, Y. M. et al. Elevated Aβ42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AβPP metabolism. Am. J. Pathol. 156, 797–805 (2000).

  76. 76.

    Zlokovic, B. V. et al. Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer’s amyloid beta. Biochem. Biophys. Res. Commun. 205, 1431–1437 (1994).

  77. 77.

    Deane, R. & Zlokovic, B. V. Role of the blood-brain barrier in the pathogenesis of Alzheimer’s disease. Curr. Alzheimer Res. 4, 191–197 (2007).

  78. 78.

    Eisele, Y. S. et al. Induction of cerebral β-amyloidosis: intracerebral versus systemic Aβ inoculation. Proc. Natl Acad. Sci. USA 106, 12926–12931 (2009).

  79. 79.

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

  80. 80.

    Bu, X. L. et al. Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies. Mol. Psychiatry 23, 1948–1956 (2018).

  81. 81.

    Wu, J. W. et al. Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J. Biol. Chem. 288, 1856–1870 (2013).

  82. 82.

    Brahic, M., Bousset, L., Bieri, G., Melki, R. & Gitler, A. D. Axonal transport and secretion of fibrillar forms of α-synuclein, Aβ42 peptide and HTTExon 1. Acta Neuropathol. 131, 539–548 (2016).

  83. 83.

    Freundt, E. C. et al. Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport. Ann. Neurol. 72, 517–524 (2012).

  84. 84.

    El-Agnaf, O. M. et al. Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J. 20, 419–425 (2006).

  85. 85.

    Mollenhauer, B. et al. Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp. Neurol. 213, 315–325 (2008).

  86. 86.

    Buch, K. et al. Tau protein. A potential biological indicator for early detection of Alzheimer disease [German]. Nervenarzt 69, 379–385 (1998).

  87. 87.

    Yamada, K. et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J. Neurosci. 31, 13110–13117 (2011).

  88. 88.

    Emmanouilidou, E. et al. Cell-produced α-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30, 6838–6851 (2010).

  89. 89.

    Alvarez-Erviti, L. et al. Lysosomal dysfunction increases exosome-mediated α-synuclein release and transmission. Neurobiol. Dis. 42, 360–367 (2011).

  90. 90.

    Shi, M. et al. Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol. 128, 639–650 (2014).

  91. 91.

    Kunadt, M. et al. Extracellular vesicle sorting of α-synuclein is regulated by sumoylation. Acta Neuropathol. 129, 695–713 (2015).

  92. 92.

    Danzer, K. M. et al. Exosomal cell-to-cell transmission of α synuclein oligomers. Mol. Neurodegener. 7, 42 (2012).

  93. 93.

    Kong, S. M. et al. Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-synuclein externalization via exosomes. Hum. Mol. Genet. 23, 2816–2833 (2014).

  94. 94.

    Tsunemi, T., Hamada, K. & Krainc, D. ATP13A2/PARK9 regulates secretion of exosomes and α-synuclein. J. Neurosci. 34, 15281–15287 (2014).

  95. 95.

    Pan-Montojo, F. et al. Environmental toxins trigger PD-like progression via increased α-synuclein release from enteric neurons in mice. Sci. Rep. 2, 898 (2012).

  96. 96.

    Poehler, A. M. et al. Autophagy modulates SNCA/α-synuclein release, thereby generating a hostile microenvironment. Autophagy 10, 2171–2192 (2014).

  97. 97.

    Ngolab, J. et al. Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology. Acta Neuropathol. Commun. 5, 46 (2017).

  98. 98.

    Saman, S. et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J. Biol. Chem. 287, 3842–3849 (2012).

  99. 99.

    Wang, Y. et al. The release and trans-synaptic transmission of Tau via exosomes. Mol. Neurodegener. 12, 5 (2017).

  100. 100.

    Vingtdeux, V. et al. Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J. Biol. Chem. 282, 18197–18205 (2007).

  101. 101.

    Sharples, R. A. et al. Inhibition of γ-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J. 22, 1469–1478 (2008).

  102. 102.

    Perez-Gonzalez, R., Gauthier, S. A., Kumar, A. & Levy, E. The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J. Biol. Chem. 287, 43108–43115 (2012).

  103. 103.

    Fiandaca, M. S. et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimers Dement. 11, 600–607.e1 (2015).

  104. 104.

    Dinkins, M. B., Dasgupta, S., Wang, G., Zhu, G. & Bieberich, E. Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol. Aging 35, 1792–1800 (2014).

  105. 105.

    An, K. et al. Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo. Mol. Brain 6, 47 (2013).

  106. 106.

    Melachroinou, K. et al. Deregulation of calcium homeostasis mediates secreted α-synuclein-induced neurotoxicity. Neurobiol. Aging 34, 2853–2865 (2013).

  107. 107.

    Ejlerskov, P. et al. Tubulin polymerization-promoting protein (TPPP/p25α) promotes unconventional secretion of α-synuclein through exophagy by impairing autophagosome-lysosome fusion. J. Biol. Chem. 288, 17313–17335 (2013).

  108. 108.

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

  109. 109.

    Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M. & Diamond, M. I. Trans-cellular propagation of Tau aggregation by fibrillar species. J. Biol. Chem. 287, 19440–19451 (2012).

  110. 110.

    Katsinelos, T. et al. Unconventional secretion mediates the trans-cellular spreading of Tau. Cell Rep. 23, 2039–2055 (2018).

  111. 111.

    Dujardin, S. et al. Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS One 9, e100760 (2014).

  112. 112.

    Davis, J. et al. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J. Biol. Chem. 279, 20296–20306 (2004).

  113. 113.

    Herzig, M. C. et al. Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat. Neurosci. 7, 954–960 (2004).

  114. 114.

    Calhoun, M. E. et al. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc. Natl Acad. Sci. USA 96, 14088–14093 (1999).

  115. 115.

    Weller, R. O. et al. Cerebral amyloid angiopathy: amyloid β accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am. J. Pathol. 153, 725–733 (1998).

  116. 116.

    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).

  117. 117.

    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).

  118. 118.

    Karpowicz, R. J. Jr. et al. Selective imaging of internalized proteopathic α-synuclein seeds in primary neurons reveals mechanistic insight into transmission of synucleinopathies. J. Biol. Chem. 292, 13482–13497 (2017).

  119. 119.

    Lee, H. J. et al. Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int. J. Biochem. Cell Biol. 40, 1835–1849 (2008).

  120. 120.

    Mao, X. et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).

  121. 121.

    Flavin, W. P. et al. Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins. Acta Neuropathol. 134, 629–653 (2017).

  122. 122.

    Calafate, S., Flavin, W., Verstreken, P. & Moechars, D. Loss of Bin1 promotes the propagation of tau pathology. Cell Rep. 17, 931–940 (2016).

  123. 123.

    Falcon, B., Noad, J., McMahon, H., Randow, F. & Goedert, M. Galectin-8-mediated selective autophagy protects against seeded tau aggregation. J. Biol. Chem. 293, 2438–2451 (2018).

  124. 124.

    Costanzo, M. et al. Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes. J. Cell Sci. 126, 3678–3685 (2013).

  125. 125.

    Abounit, S., Wu, J. W., Duff, K., Victoria, G. S. & Zurzolo, C. Tunneling nanotubes: a possible highway in the spreading of tau and other prion-like proteins in neurodegenerative diseases. Prion 10, 344–351 (2016).

  126. 126.

    Abounit, S. et al. Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes. EMBO J. 35, 2120–2138 (2016).

  127. 127.

    Rostami, J. et al. Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes. J. Neurosci. 37, 11835–11853 (2017).

  128. 128.

    Dieriks, B. V. et al. α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson’s disease patients. Sci. Rep. 7, 42984 (2017).

  129. 129.

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

  130. 130.

    Fritschi, S. K. et al. Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid. Brain 137, 2909–2915 (2014).

  131. 131.

    Marzesco, A. M. et al. Highly potent intracellular membrane-associated Aβ seeds. Sci. Rep. 6, 28125 (2016).

  132. 132.

    Takeda, S. et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat. Commun. 6, 8490 (2015).

  133. 133.

    Jackson, S. J. et al. Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S Tau. J. Neurosci. 36, 762–772 (2016).

  134. 134.

    Mirbaha, H. et al. Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife 7, e36584 (2018).

  135. 135.

    Polinski, N. K. et al. Best practices for generating and using alpha-synuclein pre-formed fibrils to model Parkinson’s disease in rodents. J. Parkinsons Dis. 8, 303–322 (2018).

  136. 136.

    Danzer, K. M., Krebs, S. K., Wolff, M., Birk, G. & Hengerer, B. Seeding induced by alpha-synuclein oligomers provides evidence for spreading of α-synuclein pathology. J. Neurochem. 111, 192–203 (2009).

  137. 137.

    Danzer, K. M. et al. Different species of α-synuclein oligomers induce calcium influx and seeding. J. Neurosci. 27, 9220–9232 (2007).

  138. 138.

    Pieri, L., Madiona, K. & Melki, R. Structural and functional properties of prefibrillar α-synuclein oligomers. Sci. Rep. 6, 24526 (2016).

  139. 139.

    Fagerqvist, T. et al. Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo. Amyloid 20, 233–244 (2013).

  140. 140.

    Guo, J. L. et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103–117 (2013).

  141. 141.

    Bousset, L. et al. Structural and functional characterization of two α-synuclein strains. Nat. Commun. 4, 2575 (2013).

  142. 142.

    Peelaerts, W. et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015).

  143. 143.

    Prusiner, S. B. et al. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc. Natl Acad. Sci. USA 112, E5308-E5317 (2015).

  144. 144.

    Woerman, A. L. et al. Propagation of prions causing synucleinopathies in cultured cells. Proc. Natl Acad. Sci. USA 112, E4949-E4958 (2015).

  145. 145.

    Lu, J. X. et al. Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell 154, 1257–1268 (2013).

  146. 146.

    Heilbronner, G. et al. Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. EMBO Rep. 14, 1017–1022 (2013).

  147. 147.

    Petkova, A. T. et al. Self-propagating, molecular-level polymorphism in Alzheimer’s β-amyloid fibrils. Science 307, 262–265 (2005).

  148. 148.

    Watts, J. C. et al. Serial propagation of distinct strains of Aβ prions from Alzheimer’s disease patients. Proc. Natl Acad. Sci. USA 111, 10323–10328 (2014).

  149. 149.

    Boluda, S. et al. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol. 129, 221–237 (2015).

  150. 150.

    Furukawa, Y., Kaneko, K., Yamanaka, K. & Nukina, N. Mutation-dependent polymorphism of Cu,Zn-superoxide dismutase aggregates in the familial form of amyotrophic lateral sclerosis. J. Biol. Chem. 285, 22221–22231 (2010).

  151. 151.

    Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).

  152. 152.

    Aguzzi, A., Heikenwalder, M. & Polymenidou, M. Insights into prion strains and neurotoxicity. Nat. Rev. Mol. Cell Biol. 8, 552–561 (2007).

  153. 153.

    Kelly, J. W. Alternative conformations of amyloidogenic proteins govern their behavior. Curr. Opin. Struct. Biol. 6, 11–17 (1996).

  154. 154.

    Dobson, C. M. Protein misfolding, evolution and disease. Trends Biochem. Sci. 24, 329–332 (1999).

  155. 155.

    Ding, F., LaRocque, J. J. & Dokholyan, N. V. Direct observation of protein folding, aggregation, and a prion-like conformational conversion. J. Biol. Chem. 280, 40235–40240 (2005).

  156. 156.

    Khare, S. D., Caplow, M. & Dokholyan, N. V. The rate and equilibrium constants for a multistep reaction sequence for the aggregation of superoxide dismutase in amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 101, 15094–15099 (2004).

  157. 157.

    Peng, Y. & Hansmann, U. H. Helix versus sheet formation in a small peptide. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 68, 041911 (2003).

  158. 158.

    Redler, R. L. & Dokholyan, N. V. The complex molecular biology of amyotrophic lateral sclerosis (ALS). Prog. Mol. Biol. Transl. Sci. 107, 215–262 (2012).

  159. 159.

    Guenther, E. L. et al. Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Nat. Struct. Mol. Biol. 25, 463–471 (2018).

  160. 160.

    Falcon, B. et al. Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 561, 137–140 (2018).

  161. 161.

    Falcon, B. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019).

  162. 162.

    Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).

  163. 163.

    Arakhamia, T. et al. Posttranslational modifications mediate the structural diversity of tauopathy strains. Cell 180, 633–644.e12 (2020).

  164. 164.

    Zhang, W. et al. Novel tau filament fold in corticobasal degeneration. Nature https://doi.org/10.1038/s41586-020-2043-0 (2020).

  165. 165.

    Cope, T. E. et al. Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy. Brain 141, 550–567 (2018).

  166. 166.

    Yamada, K. & Iwatsubo, T. Extracellular alpha-synuclein levels are regulated by neuronal activity. Mol. Neurodegener. 13, 9 (2018).

  167. 167.

    Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat. Neurosci. 19, 1085–1092 (2016).

  168. 168.

    Yamada, K. et al. Neuronal activity regulates extracellular tau in vivo. J. Exp. Med. 211, 387–393 (2014).

  169. 169.

    Bero, A. W. et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14, 750–756 (2011).

  170. 170.

    Schultz, M. K. Jr. et al. Pharmacogenetic neuronal stimulation increases human tau pathology and trans-synaptic spread of tau to distal brain regions in mice. Neurobiol. Dis. 118, 161–176 (2018).

  171. 171.

    Pooler, A. M., Phillips, E. C., Lau, D. H., Noble, W. & Hanger, D. P. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 14, 389–394 (2013).

  172. 172.

    Holth, J. K. et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363, 880–884 (2019).

  173. 173.

    Kang, J. E. et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009).

  174. 174.

    Mohamed, N. V., Desjardins, A. & Leclerc, N. Tau secretion is correlated to an increase of Golgi dynamics. PLoS One 12, e0178288 (2017).

  175. 175.

    Luo, W. et al. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci. Rep. 5, 11161 (2015).

  176. 176.

    Lee, S. J., Seo, B. R. & Koh, J. Y. Metallothionein-3 modulates the amyloid beta endocytosis of astrocytes through its effects on actin polymerization. Mol. Brain 8, 84 (2015).

  177. 177.

    Bolos, M. et al. Direct evidence of internalization of tau by microglia in vitro and in vivo. J. Alzheimers Dis. 50, 77–87 (2016).

  178. 178.

    Martini-Stoica, H. et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J. Exp. Med. 215, 2355–2377 (2018).

  179. 179.

    Yan, P. et al. Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ. J. Biol. Chem. 281, 24566–24574 (2006).

  180. 180.

    Melchor, J. P. & Strickland, S. Tissue plasminogen activator in central nervous system physiology and pathology. Thromb. Haemost. 93, 655–660 (2005).

  181. 181.

    Yamamoto, N. et al. Leptin inhibits amyloid beta-protein degradation through decrease of neprilysin expression in primary cultured astrocytes. Biochem. Biophys. Res. Commun. 445, 214–217 (2014).

  182. 182.

    Lee, C. Y. & Landreth, G. E. The role of microglia in amyloid clearance from the AD brain. J. Neural Transm. 117, 949–960 (2010).

  183. 183.

    Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).

  184. 184.

    Loria, F. et al. α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol. 134, 789–808 (2017).

  185. 185.

    Stefanova, N. et al. Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 179, 954–963 (2011).

  186. 186.

    Fellner, L. et al. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013).

  187. 187.

    Koller, E. J., Brooks, M. M., Golde, T. E., Giasson, B. I. & Chakrabarty, P. Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice. Mol. Neurodegener. 12, 1 (2017).

  188. 188.

    Park, J. Y., Paik, S. R., Jou, I. & Park, S. M. Microglial phagocytosis is enhanced by monomeric α-synuclein, not aggregated α-synuclein: implications for Parkinson’s disease. Glia 56, 1215–1223 (2008).

  189. 189.

    Lee, V. M., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159 (2001).

  190. 190.

    Williams, D. R. & Lees, A. J. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol. 8, 270–279 (2009).

  191. 191.

    Narasimhan, S. et al. Human tau pathology transmits glial tau aggregates in the absence of neuronal tau. J. Exp. Med. 217, e20190783 (2020).

  192. 192.

    Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature 552, 355–361 (2017).

  193. 193.

    Cavaliere, F. et al. In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains. Neurobiol. Dis. 103, 101–112 (2017).

  194. 194.

    Golde, T. E. Harnessing immunoproteostasis to treat neurodegenerative disorders. Neuron 101, 1003–1015 (2019).

  195. 195.

    Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018).

  196. 196.

    Song, W. M. & Colonna, M. The identity and function of microglia in neurodegeneration. Nat. Immunol. 19, 1048–1058 (2018).

  197. 197.

    Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303, 1832–1840 (2010).

  198. 198.

    Greggio, E. et al. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23, 329–341 (2006).

  199. 199.

    Healy, D. G. et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 7, 583–590 (2008).

  200. 200.

    Sheng, Z. et al. Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci. Transl. Med. 4, 164ra161 (2012).

  201. 201.

    Steger, M. et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife 5, e12813 (2016).

  202. 202.

    West, A. B. et al. Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl Acad. Sci. USA 102, 16842–16847 (2005).

  203. 203.

    Bae, E. J. et al. LRRK2 kinase regulates alpha-synuclein propagation via RAB35 phosphorylation. Nat. Commun. 9, 3465 (2018).

  204. 204.

    Zhao, H. T. et al. LRRK2 antisense oligonucleotides ameliorate alpha-synuclein inclusion formation in a Parkinson’s disease mouse model. Mol. Ther. Nucleic Acids 8, 508–519 (2017).

  205. 205.

    Henderson, M. X., Peng, C., Trojanowski, J. Q. & Lee, V. M. Y. LRRK2 activity does not dramatically alter α-synuclein pathology in primary neurons. Acta Neuropathol. Commun. 6, 45 (2018).

  206. 206.

    Volpicelli-Daley, L. A. et al. G2019S-LRRK2 expression augments α-synuclein sequestration into inclusions in neurons. J. Neurosci. 36, 7415–7427 (2016).

  207. 207.

    Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).

  208. 208.

    Sepulcre, J. et al. Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nat. Med. 24, 1910–1918 (2018).

  209. 209.

    Hamilton, R. L. Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using α-synuclein immunohistochemistry. Brain Pathol. 10, 378–384 (2000).

  210. 210.

    Irwin, D. J. et al. Neuropathologic substrates of Parkinson disease dementia. Ann. Neurol. 72, 587–598 (2012).

  211. 211.

    Sepulcre, J. et al. In vivo tau, amyloid, and gray matter profiles in the aging brain. J. Neurosci. 36, 7364–7374 (2016).

  212. 212.

    Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

  213. 213.

    Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

  214. 214.

    Jack, C. R. Jr. et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).

  215. 215.

    Jack, C. R. Jr. et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010).

  216. 216.

    Bolmont, T. et al. Induction of tau pathology by intracerebral infusion of amyloid-β-containing brain extract and by amyloid-β deposition in APP x Tau transgenic mice. Am. J. Pathol. 171, 2012–2020 (2007).

  217. 217.

    Vasconcelos, B. et al. Heterotypic seeding of Tau fibrillization by pre-aggregated Aβ provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. Acta Neuropathol. 131, 549–569 (2016).

  218. 218.

    Gotz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495 (2001).

  219. 219.

    Gomes, L. A. et al. Aβ-induced acceleration of Alzheimer-related tau-pathology spreading and its association with prion protein. Acta Neuropathol. 138, 913–941 (2019).

  220. 220.

    Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).

  221. 221.

    He, Z. et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018).

  222. 222.

    Giasson, B. I. et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300, 636–640 (2003).

  223. 223.

    Oikawa, T. et al. α-synuclein fibrils exhibit gain of toxic function, promoting tau aggregation and inhibiting microtubule assembly. J. Biol. Chem. 291, 15046–15056 (2016).

  224. 224.

    Haggerty, T. et al. Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson’s disease. Eur. J. Neurosci. 33, 1598–1610 (2011).

  225. 225.

    Wills, J. et al. Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson’s disease. PLoS One 6, e17953 (2011).

  226. 226.

    Ono, K., Takahashi, R., Ikeda, T. & Yamada, M. Cross-seeding effects of amyloid β-protein and α-synuclein. J. Neurochem. 122, 883–890 (2012).

  227. 227.

    Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q. & LaFerla, F. M. Synergistic interactions between Aβ, tau, and α-synuclein: acceleration of neuropathology and cognitive decline. J. Neurosci. 30, 7281–7289 (2010).

  228. 228.

    Masliah, E. et al. β-amyloid peptides enhance α-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 (2001).

  229. 229.

    Bassil, F. et al. Amyloid-beta (Aβ) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of Lewy body disorders with Aβ pathology. Neuron 105, 260–275 (2020).

  230. 230.

    Bachhuber, T. et al. Inhibition of amyloid-β plaque formation by α-synuclein. Nat. Med. 21, 802–807 (2015).

  231. 231.

    Spencer, B. et al. Anti-α-synuclein immunotherapy reduces α-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy. Acta Neuropathol. Commun. 5, 7 (2017).

  232. 232.

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

  233. 233.

    Games, D. et al. Reducing C-terminal-truncated α-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J. Neurosci. 34, 9441–9454 (2014).

  234. 234.

    Tran, H. T. et al. α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 7, 2054–2065 (2014).

  235. 235.

    Nobuhara, C. K. et al. Tau antibody targeting pathological species blocks neuronal uptake and interneuron propagation of tau in vitro. Am. J. Pathol. 187, 1399–1412 (2017).

  236. 236.

    Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

  237. 237.

    Bae, E. J. et al. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci. 32, 13454–13469 (2012).

  238. 238.

    Mandler, M. et al. Active immunization against α-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol. Neurodegener. 10, 10 (2015).

  239. 239.

    Masliah, E. et al. Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 46, 857–868 (2005).

  240. 240.

    Mandler, M. et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol. 127, 861–879 (2014).

  241. 241.

    Scoles, D. R. & Pulst, S. M. Oligonucleotide therapeutics in neurodegenerative diseases. RNA Biol. 15, 707–714 (2018).

  242. 242.

    Shahnawaz, M. et al. Development of a biochemical diagnosis of Parkinson disease by detection of α-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol. 74, 163–172 (2017).

  243. 243.

    Kraus, A. et al. Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease. Acta Neuropathol. 137, 585–598 (2019).

  244. 244.

    Covell, D. J. et al. Novel conformation-selective alpha-synuclein antibodies raised against different in vitro fibril forms show distinct patterns of Lewy pathology in Parkinson’s disease. Neuropathol. Appl. Neurobiol. 43, 604–620 (2017).

  245. 245.

    Gibbons, G. S. et al. Detection of Alzheimer disease (AD)-specific tau pathology in AD and nonAD tauopathies by immunohistochemistry with novel conformation-selective tau antibodies. J. Neuropathol. Exp. Neurol. 77, 216–228 (2018).

  246. 246.

    Luk, K. C. et al. Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl Acad. Sci. USA 106, 20051–20056 (2009).

  247. 247.

    Frost, B., Jacks, R. L. & Diamond, M. I. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845–12852 (2009).

  248. 248.

    Iba, M. et al. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J. Neurosci. 33, 1024–1037 (2013).

  249. 249.

    Holmes, B. B. et al. Proteopathic tau seeding predicts tauopathy in vivo. Proc. Natl Acad. Sci. USA 111, E4376-E4385 (2014).

  250. 250.

    Eisele, Y. S. et al. Multiple factors contribute to the peripheral induction of cerebral β-amyloidosis. J. Neurosci. 34, 10264–10273 (2014).

  251. 251.

    Burwinkel, M., Lutzenberger, M., Heppner, F. L., Schulz-Schaeffer, W. & Baier, M. Intravenous injection of β-amyloid seeds promotes cerebral amyloid angiopathy (CAA). Acta Neuropathol. Commun. 6, 23 (2018).

  252. 252.

    Kaufman, S. K. et al. Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92, 796–812 (2016).

  253. 253.

    Taniguchi-Watanabe, S. et al. Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol. 131, 267–280 (2016).

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The authors thank the Michael J. Fox Foundation.

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Correspondence to Virginia M.-Y. Lee.

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Glossary

Recombinant proteins

Proteins that are artificially expressed in, and purified from, bacteria.

Parabiosis

The anatomical joining of two individuals.

Microfluidic chambers

Cell culture chambers that enable the isolation of the axonal or dendritic component from cell bodies.

Ectosomes

Vesicles (0.1–1 µm in diameter) that are budded and released directly from the plasma membrane.

Direct translocation

Pore-mediated translocation across the plasma membrane.

Tunnelling nanotubes

Protrusions that extend from the plasma membrane and enable the communication of cell contents between two cells.

Protein misfolding cyclic amplification

The amplification of misfolded protein by repeated incubation with corresponding monomers.

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Peng, C., Trojanowski, J.Q. & Lee, V.M. Protein transmission in neurodegenerative disease. Nat Rev Neurol 16, 199–212 (2020). https://doi.org/10.1038/s41582-020-0333-7

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