Abstract
Many neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by the progressive appearance of abnormal proteinaceous assemblies in the nervous system. Studies in experimental systems indicate that the assemblies originate from the prion-like seeded aggregation of specific misfolded proteins that proliferate and amass to form the intracellular and/or extracellular lesions typical of each disorder. The host in which the proteopathic seeds arise provides the biochemical and physiological environment that either supports or restricts their emergence, proliferation, self-assembly, and spread. Multiple mechanisms influence the spatiotemporal spread of seeds and the nature of the resulting lesions, one of which is the cellular uptake, release, and transport of seeds along neural pathways and networks. The characteristics of cells and regions in the affected network govern their vulnerability and thereby influence the neuropathological and clinical attributes of the disease. The propagation of pathogenic protein assemblies within the nervous system is thus determined by the interaction of the proteopathic agent and the host milieu.
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References
Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 133, 571–573 (1889).
Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).
Prusiner, S. B. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601–623 (2013).
Mead, S. & Reilly, M. M. A new prion disease: relationship with central and peripheral amyloidoses. Nat. Rev. Neurol. 11, 90–97 (2015).
Imran, M. & Mahmood, S. An overview of animal prion diseases. Virol. J. 8, 493 (2011).
Imran, M. & Mahmood, S. An overview of human prion diseases. Virol. J. 8, 559 (2011).
DeArmond, S. J. & Prusiner, S. B. Etiology and pathogenesis of prion diseases. Am. J. Pathol. 146, 785–811 (1995).
Walker, L. C. & Jucker, M. Neurodegenerative diseases: expanding the prion concept. Annu. Rev. Neurosci. 38, 87–103 (2015).
Eisenberg, D. & Jucker, M. The amyloid state of proteins in human diseases. Cell 148, 1188–1203 (2012).
Collinge, J. Mammalian prions and their wider relevance in neurodegenerative diseases. Nature 539, 217–226 (2016).
Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).
Goedert, M. Neurodegeneration. Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Aβ, tau, and α-synuclein. Science 349, 1255555 (2015).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
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).
Del Tredici, K. & Braak, H. Review: sporadic Parkinson’s disease: development and distribution of α-synuclein pathology. Neuropathol. Appl. Neurobiol. 42, 33–50 (2016).
Saper, C. B., Wainer, B. H. & German, D. C. Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer’s disease. Neuroscience 23, 389–398 (1987).
Iturria-Medina, Y. & Evans, A. C. On the central role of brain connectivity in neurodegenerative disease progression. Front. Aging Neurosci. 7, 90 (2015).
Palmqvist, S. et al. Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat. Commun. 8, 1214 (2017).
Kane, M. D. et al. Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice. J. Neurosci. 20, 3606–3611 (2000).
Meyer-Luehmann, M. et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).
Langer, F. et al. Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J. Neurosci. 31, 14488–14495 (2011).
Morales, R., Duran-Aniotz, C., Castilla, J., Estrada, L. D. & Soto, C. De novo induction of amyloid-β deposition in vivo. Mol. Psychiatry 17, 1347–1353 (2012).
Fritschi, S. K. et al. Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid. Brain 137, 2909–2915 (2014).
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).
Rasmussen, J. et al. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 114, 13018–13023 (2017).
Ruiz-Riquelme, A. et al. Prion-like propagation of β-amyloid aggregates in the absence of APP overexpression. Acta Neuropathol. Commun. 6, 26 (2018).
Aguzzi, A. & Calella, A. M. Prions: protein aggregation and infectious diseases. Physiol. Rev. 89, 1105–1152 (2009).
Hamaguchi, T. et al. The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol. 123, 31–37 (2012).
Ye, L. et al. Progression of seed-induced Aβ deposition within the limbic connectome. Brain Pathol. 25, 743–752 (2015).
Domert, J. et al. Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiol. Dis. 65, 82–92 (2014).
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).
Marzesco, A. M. et al. Highly potent intracellular membrane-associated Aβ seeds. Sci. Rep. 6, 28125 (2016).
Eisele, Y. S. et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 330, 980–982 (2010).
Eisele, Y. S. et al. Multiple factors contribute to the peripheral induction of cerebral β-amyloidosis. J. Neurosci. 34, 10264–10273 (2014).
Burwinkel, M., Lutzenberger, M., Heppner, F. L., Schulz-Schaeffer, W. & Baier, M. Intravenous injection of beta-amyloid seeds promotes cerebral amyloid angiopathy (CAA). Acta Neuropathol. Commun. 6, 23 (2018).
Jaunmuktane, Z. et al. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525, 247–250 (2015).
Brown, P. et al. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg. Infect. Dis. 18, 901–907 (2012).
Cali, I. et al. Iatrogenic Creutzfeldt-Jakob disease with amyloid-β pathology: an international study. Acta Neuropathol. Commun. 6, 5 (2018).
Will, R. G. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. Br. Med. Bull. 66, 255–265 (2003).
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).
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).
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).
Hervé, 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).
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 Abeta pathology. Acta Neuropathol. 135, 201–212 (2018).
Kovacs, G. G. et al. Dura mater is a potential source of Aβ seeds. Acta Neuropathol. 131, 911–923 (2016).
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).
Rasmussen, J. et al. Infectious prions do not induce Aβ deposition in an in vivo seeding model. Acta Neuropathol. 135, 965–967 (2018).
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).
Spillantini, M. G. & Goedert, M. Tau pathology and neurodegeneration. Lancet Neurol. 12, 609–622 (2013).
Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).
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).
Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl. Acad. Sci. USA 110, 9535–9540 (2013).
Lasagna-Reeves, C. A. et al. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci. Rep. 2, 700 (2012).
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).
Iba, M. et al. Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections. Acta Neuropathol. 130, 349–362 (2015).
Ahmed, Z. et al. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 127, 667–683 (2014).
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).
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).
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).
Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).
Clavaguera, F. et al. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 127, 299–301 (2014).
de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697 (2012).
Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLoS One 7, e31302 (2012).
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).
Irwin, D. J. et al. Deep clinical and neuropathological phenotyping of Pick disease. Ann. Neurol. 79, 272–287 (2016).
McKee, A. C. et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64 (2013).
Dubois, B. et al. Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimers Dement. 12, 292–323 (2016).
Götz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495 (2001).
Bolmont, T. et al. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am. J. Pathol. 171, 2012–2020 (2007).
Pooler, A. M. et al. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathol. Commun. 3, 14 (2015).
Li, T. et al. The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model. Nat. Commun. 7, 12082 (2016).
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).
Vasconcelos, B. et al. Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. Acta Neuropathol. 131, 549–569 (2016).
Busche, M. A. et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 109, 8740–8745 (2012).
Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat. Neurosci. 19, 1085–1092 (2016).
Goedert, M., Spillantini, M. G., Del Tredici, K. & Braak, H. 100 years of Lewy pathology. Nat. Rev. Neurol. 9, 13–24 (2013).
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).
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).
Mougenot, A. L. et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33, 2225–2228 (2012).
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).
Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).
Masuda-Suzukake, M. et al. Pathological alpha-synuclein propagates through neural networks. Acta Neuropathol. Commun. 2, 88 (2014).
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).
Peng, C. et al. Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature 557, 558–563 (2018).
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).
Masuda-Suzukake, M. et al. Prion-like spreading of pathological α-synuclein in brain. Brain 136, 1128–1138 (2013).
Rey, N. L. et al. Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J. Exp. Med. 213, 1759–1778 (2016).
Sacino, A. N. et al. Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc. Natl. Acad. Sci. USA 111, 10732–10737 (2014).
Peelaerts, W. et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015).
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).
Sargent, D. et al. ‘Prion-like’ propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum. J. Neurochem. 143, 126–135 (2017).
Parkinson, J. An essay on the shaking palsy. 1817. J. Neuropsychiatry Clin. Neurosci. 14, 223–236 (2002). discussion 222.
Braak, H., de Vos, R. A., Bohl, J. & Del Tredici, K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci. Lett. 396, 67–72 (2006).
Ayers, J. I. et al. Experimental transmissibility of mutant SOD1 motor neuron disease. Acta Neuropathol. 128, 791–803 (2014).
Porta, Y.X. et al. Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat. Commun. (in the press).
Zhou, Q. et al. Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins. EMBO Mol. Med. 9, 687–702 (2017).
Collinge, J. & Clarke, A. R. A general model of prion strains and their pathogenicity. Science 318, 930–936 (2007).
Li, J., Browning, S., Mahal, S. P., Oelschlegel, A. M. & Weissmann, C. Darwinian evolution of prions in cell culture. Science 327, 869–872 (2010).
Tanaka, M., Collins, S. R., Toyama, B. H. & Weissman, J. S. The physical basis of how prion conformations determine strain phenotypes. Nature 442, 585–589 (2006).
Qiang, W., Yau, W. M., Lu, J. X., Collinge, J. & Tycko, R. Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes. Nature 541, 217–221 (2017).
Condello, C. et al. Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 115, E782–E791 (2018).
Di Fede, G. et al. Molecular subtypes of Alzheimer’s disease. Sci. Rep. 8, 3269 (2018).
Cohen, M. L. et al. Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-β. Brain 138, 1009–1022 (2015).
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).
Gremer, L. et al. Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science 358, 116–119 (2017).
Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).
Heilbronner, G. et al. Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. EMBO Rep. 14, 1017–1022 (2013).
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).
Guo, J. L. et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103–117 (2013).
Woerman, A. L. et al. Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication. Proc. Natl. Acad. Sci. USA 115, 409–414 (2018).
Wille, H. & Requena, J. R. The structure of PrPSc prions. Pathogens 7, E20 (2018).
Fritschi, S. K. et al. Aβ seeds resist inactivation by formaldehyde. Acta Neuropathol. 128, 477–484 (2014).
Kaufman, S. K., Thomas, T. L., Del Tredici, K., Braak, H. & Diamond, M. I. Characterization of tau prion seeding activity and strains from formaldehyde-fixed tissue. Acta Neuropathol. Commun. 5, 41 (2017).
Schweighauser, M. et al. Formaldehyde-fixed brain tissue from spontaneously ill α-synuclein transgenic mice induces fatal α-synucleinopathy in transgenic hosts. Acta Neuropathol. 129, 157–159 (2015).
Woerman, A. L. et al. MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol. 135, 49–63 (2018).
Eisele, Y. S. et al. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc. Natl. Acad. Sci. USA 106, 12926–12931 (2009).
Ye, L. et al. Persistence of Aβ seeds in APP null mouse brain. Nat. Neurosci. 18, 1559–1561 (2015).
Diack, A. B. et al. Insights into mechanisms of chronic neurodegeneration. Int. J. Mol. Sci. 17, E82 (2016).
Kim, C. et al. Small protease sensitive oligomers of PrPSc in distinct human prions determine conversion rate of PrP(C). PLoS Pathog. 8, e1002835 (2012).
Silveira, J. R. et al. The most infectious prion protein particles. Nature 437, 257–261 (2005).
Gerson, J. et al. Tau oligomers derived from traumatic brain injury cause cognitive impairment and accelerate onset of pathology in hTau mice. J. Neurotrauma 33, 2034–2043 (2016).
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).
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).
Falcon, B. et al. Conformation determines the seeding potencies of native and recombinant Tau aggregates. J. Biol. Chem. 290, 1049–1065 (2015).
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).
Stöhr, J. et al. Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions. Proc. Natl. Acad. Sci. USA 109, 11025–11030 (2012).
Supattapone, S. Synthesis of high titer infectious prions with cofactor molecules. J. Biol. Chem. 289, 19850–19854 (2014).
Novotny, R. et al. Conversion of synthetic Aβ to in vivo active seeds and amyloid plaque formation in a hippocampal slice culture model. J. Neurosci. 36, 5084–5093 (2016).
Labbadia, J. & Morimoto, R. I. The biology of proteostasis in aging and disease. Annu. Rev. Biochem. 84, 435–464 (2015).
Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Parkinson’s disease is not simply a prion disorder. J. Neurosci. 37, 9799–9807 (2017).
Mattsson, N., Schott, J. M., Hardy, J., Turner, M. R. & Zetterberg, H. Selective vulnerability in neurodegeneration: insights from clinical variants of Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 87, 1000–1004 (2016).
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).
Mezias, C. & Raj, A. Analysis of amyloid-β pathology spread in mouse models suggests spread is driven by spatial proximity, not connectivity. Front. Neurol. 8, 653 (2017).
Hu, P. P. et al. Role of prion replication in the strain-dependent brain regional distribution of prions. J. Biol. Chem. 291, 12880–12887 (2016).
Freer, R. et al. A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease. Sci. Adv. 2, e1600947 (2016).
Rangel, A. et al. Distinct patterns of spread of prion infection in brains of mice expressing anchorless or anchored forms of prion protein. Acta Neuropathol. Commun. 2, 8 (2014).
Mao, X. et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).
Lee, J. G., Takahama, S., Zhang, G., Tomarev, S. I. & Ye, Y. Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells. Nat. Cell Biol. 18, 765–776 (2016).
Katsinelos, T. et al. Unconventional secretion mediates the trans-cellular spreading of tau. Cell Rep. 23, 2039–2055 (2018).
Ye, L. et al. Aβ seeding potency peaks in the early stages of cerebral β-amyloidosis. EMBO Rep. 18, 1536–1544 (2017).
Bero, A. W. et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14, 750–756 (2011).
Yamada, K. et al. Neuronal activity regulates extracellular tau in vivo. J. Exp. Med. 211, 387–393 (2014).
Yamada, K. & Iwatsubo, T. Extracellular α-synuclein levels are regulated by neuronal activity. Mol. Neurodegener. 13, 9 (2018).
Phinney, A. L. et al. Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice. J. Neurosci. 19, 8552–8559 (1999).
Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017).
Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355–361 (2017).
DeVos, S. L. et al. Synaptic tau seeding precedes tau pathology in human Alzheimer’s disease brain. Front. Neurosci. 12, 267 (2018).
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. https://doi.org/10.1007/s00401-018-1855-6 (2018).
Shen, M. M. Cancer: the complex seeds of metastasis. Nature 520, 298–299 (2015).
Cicchetti, F. et al. Mutant huntingtin is present in neuronal grafts in huntington disease patients. Ann. Neurol. 76, 31–42 (2014).
Jeon, I. et al. Human-to-mouse prion-like propagation of mutant huntingtin protein. Acta Neuropathol. 132, 577–592 (2016).
Acknowledgements
We thank J. Rasmussen, M. Bacioglu, and the members of our laboratories for critical discussions and comments. The help of A. Apel and G. Rose with the manuscript and figures is gratefully acknowledged. Supported by the EC Joint Programme on Neurodegenerative Diseases under the Grants JPND-NewTargets and JPND-REfrAME (M.J.), Horizon 2020 IMPRiND (M.J.), National Institutes of Health (NIH) grants P50 AG025688 and ORIP/OD P51OD011132, and by the Alexander von Humboldt Foundation (L.C.W.).
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Jucker, M., Walker, L.C. Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nat Neurosci 21, 1341–1349 (2018). https://doi.org/10.1038/s41593-018-0238-6
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DOI: https://doi.org/10.1038/s41593-018-0238-6
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