{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:52:59Z","timestamp":1790362379116,"version":"4.1.0"},"reference-count":140,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AB002132"],"award-info":[{"award-number":["AB002132"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Brockman Foundation","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/100011756","name":"Sherman Fairchild Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100011756","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer\u2019s disease (AD), Parkinson\u2019s disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt\u2013Jakob disease (CJD) and Gerstmann\u2013Str\u00e4ussler\u2013Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived A\u03b2 peptides, tau, and \u03b1-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field.<\/jats:p>","DOI":"10.3390\/ijms22094861","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T11:06:01Z","timestamp":1620212761000},"page":"4861","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["How an Infection of Sheep Revealed Prion Mechanisms in Alzheimer\u2019s Disease and Other Neurodegenerative Disorders"],"prefix":"10.3390","volume":"22","author":[{"given":"George A.","family":"Carlson","sequence":"first","affiliation":[{"name":"Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158, USA"},{"name":"Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley B.","family":"Prusiner","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158, USA"},{"name":"Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158, USA"},{"name":"Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1126\/science.6801762","article-title":"Novel proteinaceous infectious particles cause scrapie","volume":"216","author":"Prusiner","year":"1982","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1073\/pnas.95.23.13363","article-title":"Prions","volume":"95","author":"Prusiner","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","unstructured":"Prusiner, S.B. (2017). An introduction to \"Prion Biology\". Prion Biology, Cold Spring Harbor Laboratory Press."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1042\/ETLS20200037","article-title":"Expanding spectrum of prion diseases","volume":"4","author":"Ayers","year":"2020","journal-title":"Emerg. Top. Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/bs.pmbts.2017.06.007","article-title":"Prion protein and genetic susceptibility to diseases caused by its misfolding","volume":"150","author":"Carlson","year":"2017","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_6","unstructured":"Prusiner, S.B. (2017). Neurodegenerative disease transmission and transgenesis in mice. Prion Biology, Cold Spring Harbor Laboratory Press."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature15369","article-title":"Evidence for human transmission of amyloid-\u03b2 pathology and cerebral amyloid angiopathy","volume":"525","author":"Jaunmuktane","year":"2015","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41586-018-0790-y","article-title":"Transmission of amyloid-\u03b2 protein pathology from cadaveric pituitary growth hormone","volume":"564","author":"Purro","year":"2018","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1007\/s00702-005-0385-2","article-title":"Very long term studies of the seeding of beta-amyloidosis in primates","volume":"113","author":"Ridley","year":"2006","journal-title":"J. Neural Transm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-propagation of pathogenic protein aggregates in neurodegenerative diseases","volume":"501","author":"Jucker","year":"2013","journal-title":"Nature"},{"key":"ref_11","unstructured":"Prusiner, S.B. (2017). The prion-like behavior of assembled tau in transgenic mice. Prion Diseases, Cold Spring Harbor Laboratory Press."},{"key":"ref_12","unstructured":"Prusiner, S.B. (2017). Cellular models for the study of prions. Prion Diseases, Cold Spring Harbor Laboratory Press."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E8187","DOI":"10.1073\/pnas.1616344113","article-title":"Tau prions from Alzheimer\u2019s disease and chronic traumatic encephalopathy patients propagate in cultured cells","volume":"113","author":"Woerman","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19555","DOI":"10.1073\/pnas.1318268110","article-title":"Transmission of multiple system atrophy prions to transgenic mice","volume":"110","author":"Watts","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E4949","DOI":"10.1073\/pnas.1513426112","article-title":"Propagation of prions causing synucleinopathies in cultured cells","volume":"112","author":"Woerman","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.brainresbull.2008.09.012","article-title":"The early history of the transmissible spongiform encephalopathies exemplified by scrapie","volume":"77","author":"Schneider","year":"2008","journal-title":"Brain Res. Bull."},{"key":"ref_17","first-page":"1552","article-title":"La maladie dite tremblante du mouton est-elle inoculable?","volume":"203","author":"Chelle","year":"1936","journal-title":"C. R. Acad. Sci."},{"key":"ref_18","first-page":"1058","article-title":"Transmission experimentale de la tremblante a la chevre","volume":"208","author":"Chelle","year":"1939","journal-title":"C. R. Acad. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/0006-291X(66)90478-5","article-title":"The exceptionally small size of the scrapie agent","volume":"22","author":"Alper","year":"1966","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/214764a0","article-title":"Does the agent of scrapie replicate without nucleic acid?","volume":"214","author":"Alper","year":"1967","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1038\/2271341a0","article-title":"Inactivation of the scrapie agent by near monochromatic ultraviolet light","volume":"227","author":"Latarjet","year":"1970","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1146\/annurev.mi.43.100189.002021","article-title":"Scrapie prions","volume":"43","author":"Prusiner","year":"1989","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_23","unstructured":"Prusiner, S.B. (2017). Prion Biology, Cold Spring Harbor Laboratory Press."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1056\/NEJM195711142572005","article-title":"Degenerative disease of the central nervous system in New Guinea; The endemic occurrence of \u201ckuru\u201d in the native population","volume":"257","author":"Gajdusek","year":"1957","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/0002-9343(59)90251-7","article-title":"Kuru\u2014Clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the eastern highlands of New Guinea","volume":"26","author":"Gajdusek","year":"1959","journal-title":"Am. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0140-6736(59)92081-1","article-title":"Scrapie and kuru","volume":"274","author":"Hadlow","year":"1959","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/209794a0","article-title":"Experimental transmission of a kuru-like syndrome to chimpanzees","volume":"209","author":"Gajdusek","year":"1966","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1097\/NEN.0b013e318232a379","article-title":"Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years","volume":"70","author":"Braak","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.neuron.2011.11.033","article-title":"Propagation of tau pathology in a model of early Alzheimer\u2019s disease","volume":"73","author":"Polydoro","year":"2012","journal-title":"Neuron"},{"key":"ref_30","first-page":"516","article-title":"Advances in veterinary research","volume":"58","author":"Gordon","year":"1946","journal-title":"Vet. Rec."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0021-9975(65)90006-X","article-title":"Resistance of the scrapie agent to formalin","volume":"75","author":"Pattison","year":"1965","journal-title":"J. Comp. Pathol."},{"key":"ref_32","first-page":"58","article-title":"Attempts to demonstrate antibodies in scrapie disease","volume":"71","author":"Chandler","year":"1959","journal-title":"Vet. Rec."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0007-1935(17)50172-4","article-title":"Rida, a chronic encephalitis of sheep with general remarks on infections which develop slowly and some of their special characteristics","volume":"110","author":"Sigurdsson","year":"1954","journal-title":"Br. Vet. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1126\/science.142303","article-title":"Unconventional viruses and the origin and disappearance of kuru","volume":"197","author":"Gajdusek","year":"1977","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/2151043a0","article-title":"Nature of the scrapie agent: Self-replication and scrapie","volume":"215","author":"Griffith","year":"1967","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/vr.80.1.2","article-title":"The possible nature of the transmissible agent of scrapie","volume":"80","author":"Pattison","year":"1967","journal-title":"Vet. Rec."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.6815801","article-title":"Identification of a protein that purifies with the scrapie prion","volume":"218","author":"Bolton","year":"1982","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/0092-8674(85)90333-2","article-title":"A cellular gene encodes scrapie PrP 27\u201330 protein","volume":"40","author":"Oesch","year":"1985","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/0092-8674(86)90875-5","article-title":"Linkage of prion protein and scrapie incubation time genes","volume":"46","author":"Carlson","year":"1986","journal-title":"Cell"},{"key":"ref_40","first-page":"5528","article-title":"Genetics and polymorphism of the mouse prion gene complex: Control of scrapie incubation time","volume":"8","author":"Carlson","year":"1988","journal-title":"Mol. Cell. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/0092-8674(87)90134-6","article-title":"Distinct prion proteins in short and long scrapie incubation period mice","volume":"51","author":"Westaway","year":"1987","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1093\/genetics\/133.4.979","article-title":"Delimiting the location of the scrapie prion incubation time gene on chromosome 2 of the mouse","volume":"133","author":"Carlson","year":"1993","journal-title":"Genetics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/ng0298-118","article-title":"Mice with gene targetted prion protein alterations show that Prnp, Sinc and Prni are congruent","volume":"18","author":"Moore","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/hdy.1964.31","article-title":"Genetical control of the incubation period in mice of the neurological disease, scrapie","volume":"19","author":"Dickinson","year":"1964","journal-title":"Heredity"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/BF00266934","article-title":"Host-genotype and agent effects in scrapie incubation: Change in allelic interaction with different strains of agent","volume":"112","author":"Dickinson","year":"1971","journal-title":"Mol. Gen. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1017\/S0016672300002895","article-title":"A comparison of some biological characteristics of the mouse-passaged scrapie agents, 22A and ME7","volume":"13","author":"Dickinson","year":"1969","journal-title":"Genet. Res."},{"key":"ref_47","first-page":"125","article-title":"Scrapie strain variation and its implications","volume":"172","author":"Bruce","year":"1991","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7475","DOI":"10.1073\/pnas.86.19.7475","article-title":"Primary structure of prion protein may modify scrapie isolate properties","volume":"86","author":"Carlson","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0896-6273(91)90074-A","article-title":"Paradoxical shortening of scrapie incubation times by expression of prion protein transgenes derived from long incubation period mice","volume":"7","author":"Westaway","year":"1991","journal-title":"Neuron"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5690","DOI":"10.1073\/pnas.91.12.5690","article-title":"Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice","volume":"91","author":"Carlson","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0021-9975(65)90005-8","article-title":"Experimental transmission of mouse passaged scrapie to goats, sheep, rats and hamsters","volume":"75","author":"Zlotnik","year":"1965","journal-title":"J. Comp. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1099\/0022-1317-42-1-107","article-title":"Pathogenesis of scrapie: Agent multiplication in brain at the first and second passage of hamster scrapie in mice","volume":"42","author":"Kimberlin","year":"1979","journal-title":"J. Gen. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/0092-8674(89)90608-9","article-title":"Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques","volume":"59","author":"Scott","year":"1989","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/0092-8674(90)90134-Z","article-title":"Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication","volume":"63","author":"Prusiner","year":"1990","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/338342a0","article-title":"Linkage of a prion protein missense variant to Gerstmann-Str\u00e4ussler syndrome","volume":"338","author":"Hsiao","year":"1989","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1126\/science.1980379","article-title":"Spontaneous neurodegeneration in transgenic mice with mutant prion protein","volume":"250","author":"Hsiao","year":"1990","journal-title":"Science"},{"key":"ref_57","unstructured":"Prusiner, S.B., Collinge, J., Powell, J., and Anderton, B. (1992). Genetic and transgenic studies of prion proteins in Gerstmann-Straussler\u2013Scheinker disease. Prion Diseases of Humans and Animals, Ellis Horwood."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1056\/NEJM198509193131205","article-title":"Potential epidemic of Creutzfeldt-Jakob disease from human growth hormone therapy","volume":"313","author":"Brown","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1056\/NEJM199104183241604","article-title":"Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease","volume":"324","author":"Hsiao","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1056\/NEJM199202133260704","article-title":"Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene","volume":"326","author":"Medori","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref_61","unstructured":"Minikel, E.V., Vallabh, S.M., Lek, M., Estrada, K., Samocha, K.E., Sathirapongsasuti, J.F., McLean, C.Y., Tung, J.Y., Yu, L.P.C., and Gambetti, P. (2016). Quantifying prion disease penetrance using large population control cohorts. Sci. Transl. Med., 8."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1099\/0022-1317-73-2-329","article-title":"Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters","volume":"73","author":"Bessen","year":"1992","journal-title":"J. Gen. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"7859","DOI":"10.1128\/jvi.68.12.7859-7868.1994","article-title":"Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy","volume":"68","author":"Bessen","year":"1994","journal-title":"J. Virol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/375698a0","article-title":"Non-genetic propagation of strain-specific properties of scrapie prion protein","volume":"375","author":"Bessen","year":"1995","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1126\/science.274.5295.2079","article-title":"Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity","volume":"274","author":"Telling","year":"1996","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1099\/0022-1317-72-3-595","article-title":"The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: Implications for the nature of the agent and host control of pathogenesis","volume":"72","author":"Bruce","year":"1991","journal-title":"J. Gen. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1126\/science.278.5336.245","article-title":"Prion diseases and the BSE crisis","volume":"278","author":"Prusiner","year":"1997","journal-title":"Science"},{"key":"ref_68","first-page":"E87","article-title":"Clinical features of sporadic fatal insomnia","volume":"6","author":"Barash","year":"2009","journal-title":"Rev. Neurol. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1016\/S0140-6736(06)68930-7","article-title":"Kuru in the 21st century\u2014An acquired human prion disease with very long incubation periods","volume":"367","author":"Collinge","year":"2006","journal-title":"Lancet"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1056\/NEJMoa0809716","article-title":"A novel protective prion protein variant that colocalizes with kuru exposure","volume":"361","author":"Mead","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/nature14510","article-title":"A naturally occurring variant of the human prion protein completely prevents prion disease","volume":"522","author":"Asante","year":"2015","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1126\/science.1183218","article-title":"Darwinian evolution of prions in cell culture","volume":"327","author":"Li","year":"2010","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"E4160","DOI":"10.1073\/pnas.1317164110","article-title":"Drug resistance confounding prion therapeutics","volume":"110","author":"Berry","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Oelschlegel, A.M., and Weissmann, C. (2013). Acquisition of drug resistance and dependence by prions. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003158"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"12571","DOI":"10.1073\/pnas.0906759106","article-title":"Is Parkinson\u2019s disease a prion disorder?","volume":"106","author":"Olanow","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/ncb1901","article-title":"Transmission and spreading of tauopathy in transgenic mouse brain","volume":"11","author":"Clavaguera","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1084\/jem.20112457","article-title":"Intracerebral inoculation of pathological \u03b1-synuclein initiates a rapidly progressive neurodegenerative \u03b1-synucleinopathy in mice","volume":"209","author":"Luk","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_78","unstructured":"Prusiner, S.B. (2017). \u03b1-Synuclein: Multiple system atrophy prions. Prion Diseases, Cold Spring Harbor Laboratory Press."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1146\/annurev-genet-110711-155524","article-title":"Biology and genetics of prions causing neurodegeneration","volume":"47","author":"Prusiner","year":"2013","journal-title":"Annu. Rev. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature20415","article-title":"Mammalian prions and their wider relevance in neurodegenerative diseases","volume":"539","author":"Collinge","year":"2016","journal-title":"Nature"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"10323","DOI":"10.1073\/pnas.1408900111","article-title":"Serial propagation of distinct strains of A\u03b2 prions from Alzheimer\u2019s disease patients","volume":"111","author":"Watts","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1007\/BF02866241","article-title":"\u00dcber eigenartige Krankheitsf\u00e4lle des sp\u00e4teren Alters","volume":"4","author":"Alzheimer","year":"1911","journal-title":"Zentralbl. Gesamte Neurol. Psychiatr."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5991","DOI":"10.1073\/pnas.84.16.5991","article-title":"Hereditary cerebral haemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer\u2019s disease","volume":"84","author":"Castano","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00401-004-0824-4","article-title":"Glial reactions and the clearance of amyloid \u03b2 protein in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type","volume":"107","author":"Yamaguchi","year":"2004","journal-title":"Acta Neuropathol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1073\/pnas.82.12.4245","article-title":"Amyloid plaque core protein in Alzheimer disease and Down syndrome","volume":"82","author":"Masters","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1126\/science.3810169","article-title":"Charaterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer\u2019s disease","volume":"235","author":"Goldgaber","year":"1987","journal-title":"Science"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/349704a0","article-title":"Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease","volume":"349","author":"Goate","year":"1991","journal-title":"Nature"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nm0797-723","article-title":"Serpents on the road to dementia and death. Accumulating evidence from several studies points to the normal function of presenilin 1 and suggests how the mutant protein contributes to deposition of amyloid plaques in Alzheimer\u2019s disease","volume":"3","author":"Beyreuther","year":"1997","journal-title":"Nat. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1471-4159.2011.07575.x","article-title":"Twenty years of Alzheimer\u2019s disease-causing mutations","volume":"120","author":"Goate","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1212\/WNL.30.9.945","article-title":"Evidence for and against the transmissibility of Alzheimer\u2019s disease","volume":"30","author":"Goudsmit","year":"1980","journal-title":"Neurology"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Godec, M.S., Asher, D.M., Masters, C.L., Kozachuk, W.E., Friedland, R.P., Gibbs, C.J., Gajdusek, D.C., Rapoport, S.I., and Schapiro, M.B. (1991). Evidence against the transmissibility of Alzheimer\u2019s disease. Neurology, 41.","DOI":"10.1212\/WNL.41.8.1320"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/BF02778005","article-title":"Induction of \u00df(A4)-amyloid in primates by injection of Alzheimer\u2019s disease brain homogenate","volume":"8","author":"Baker","year":"1994","journal-title":"Mol. Neurobiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1126\/science.1131864","article-title":"Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host","volume":"313","author":"Coomaraswamy","year":"2006","journal-title":"Science"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"12926","DOI":"10.1073\/pnas.0903200106","article-title":"Induction of cerebral \u03b2-amyloidosis: Intracerebral versus systemic A\u03b2 inoculation","volume":"106","author":"Eisele","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1126\/science.1194516","article-title":"Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis","volume":"330","author":"Eisele","year":"2010","journal-title":"Science"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"10329","DOI":"10.1073\/pnas.1408968111","article-title":"Distinct synthetic A\u03b2 prion strains producing different amyloid deposits in bigenic mice","volume":"111","author":"Condello","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"9126","DOI":"10.1073\/pnas.91.19.9126","article-title":"Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein","volume":"91","author":"Hsiao","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1001\/archneur.56.3.357","article-title":"Creutzfeldt-Jakob disease with florid-type plaques after cadaveric dura mater grafting","volume":"56","author":"Shimizu","year":"1999","journal-title":"Arch. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.jpeds.2003.12.036","article-title":"Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients","volume":"144","author":"Mills","year":"2004","journal-title":"J. Pediatr."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Aoyagi, A., Condello, C., St\u00f6hr, J., Yue, W., Lee, J.C., Rivera, B.M., Woerman, A.L., Halliday, G., van Duinen, S., and Ingelsson, M. (2019). A\u03b2 and tau prion-like activities decline with longevity in the Alzheimer\u2019s disease human brain. Sci. Transl. Med., 11.","DOI":"10.1126\/scitranslmed.aat8462"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1073\/pnas.72.5.1858","article-title":"A protein factor essential for microtubule assembly","volume":"75","author":"Weingarten","year":"1975","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/0896-6273(89)90210-9","article-title":"Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer\u2019s disease","volume":"3","author":"Goedert","year":"1989","journal-title":"Neuron"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/j.1460-2075.1989.tb03390.x","article-title":"Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: Differential expression of tau protein mRNAs in human brain","volume":"8","author":"Goedert","year":"1989","journal-title":"EMBO J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"10626","DOI":"10.1021\/bi00158a027","article-title":"Structure and novel exons of the human \u03c4 gene","volume":"31","author":"Andreadis","year":"1992","journal-title":"Biochemistry"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/31508","article-title":"Association of missense and 5\u2019-splice-site mutations in tau with the inherited dementia FTDP-17","volume":"393","author":"Hutton","year":"1998","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1750-3639.1998.tb00162.x","article-title":"Frontotemporal dementia and parkinsonism linked to chromosome 17: A new group of tauopathies","volume":"8","author":"Spillantini","year":"1998","journal-title":"Brain Pathol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0014-5793(99)00210-0","article-title":"Polymerization of tau peptides into fibrillar structures. The effect of FTDP-17 mutations","volume":"446","author":"Arrasate","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0014-5793(99)00294-X","article-title":"Accelerated filament formation from tau protein with specific FTDP-17 missense mutations","volume":"447","author":"Nacharaju","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological staging of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Ossenkoppele, R., Iaccarino, L., Schonhaut, D.R., Brown, J.A., La Joie, R., O\u2019Neil, J.P., Janabi, M., Baker, S.L., Kramer, J.H., and Gorno-Tempini, M.L. (2019). Tau covariance patterns in Alzheimer\u2019s disease patients match intrinsic connectivity networks in the healthy brain. Neuroimage Clin., 23.","DOI":"10.1016\/j.nicl.2019.101848"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Franzmeier, N., Neitzel, J., Rubinski, A., Smith, R., Strandberg, O., Ossenkoppele, R., Hansson, O., Ewers, M., and Alzheimer\u2019s Disease Neuroimaging Initiative (2020). Functional brain architecture is associated with the rate of tau accumulation in Alzheimer\u2019s disease. Nat. Commun., 11.","DOI":"10.1038\/s41467-019-14159-1"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Vogel, J.W., Iturria-Medina, Y., Strandberg, O.T., Smith, R., Levitis, E., Evans, A.C., Hansson, O., Alzheimer\u2019s Disease Neuroimaging Initiative, and Swedish BioFinder Study (2020). Spread of pathological tau proteins through communicating neurons in human Alzheimer\u2019s disease. Nat. Commun., 11.","DOI":"10.1101\/555821"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"19440","DOI":"10.1074\/jbc.M112.346072","article-title":"Trans-cellular propagation of Tau aggregation by fibrillar species","volume":"287","author":"Kfoury","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.neuron.2014.04.047","article-title":"Distinct tau prion strains propagate in cells and mice and define different tauopathies","volume":"82","author":"Sanders","year":"2014","journal-title":"Neuron"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"He, Z., McBride, J.D., Xu, H., Changolkar, L., Kim, S.J., Zhang, B., Narasimhan, S., Gibbons, G.S., Guo, J.L., and Kozak, M. (2020). Transmission of tauopathy strains is independent of their isoform composition. Nat. Commun., 11.","DOI":"10.1038\/s41467-019-13787-x"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nature23002","article-title":"Cryo-EM structures of tau filaments from Alzheimer\u2019s disease","volume":"547","author":"Fitzpatrick","year":"2017","journal-title":"Nature"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41586-018-0454-y","article-title":"Structures of filaments from Pick\u2019s disease reveal a novel tau protein fold","volume":"561","author":"Falcon","year":"2018","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/s41586-019-1026-5","article-title":"Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules","volume":"568","author":"Falcon","year":"2019","journal-title":"Nature"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41586-020-2043-0","article-title":"Novel tau filament fold in corticobasal degeneration","volume":"580","author":"Zhang","year":"2020","journal-title":"Nature"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"9535","DOI":"10.1073\/pnas.1301175110","article-title":"Brain homogenates from human tauopathies induce tau inclusions in mouse brain","volume":"110","author":"Clavaguera","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1523\/JNEUROSCI.2642-12.2013","article-title":"Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer\u2019s-like tauopathy","volume":"33","author":"Iba","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1126\/science.1062097","article-title":"Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils","volume":"293","author":"Gotz","year":"2001","journal-title":"Science"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1126\/science.1058189","article-title":"Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP","volume":"293","author":"Lewis","year":"2001","journal-title":"Science"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1016\/j.ajpath.2017.03.011","article-title":"Enhanced tau aggregation in the presence of amyloid \u03b2","volume":"187","author":"Bennett","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nm.4443","article-title":"Amyloid-\u03b2 plaques enhance Alzheimer\u2019s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation","volume":"24","author":"He","year":"2018","journal-title":"Nat. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","article-title":"Mutation in the \u03b1-synuclein gene identified in families with Parkinson\u2019s disease","volume":"276","author":"Polymeropoulos","year":"1997","journal-title":"Science"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"\u03b1-Synuclein in Lewy bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0304-3940(98)00504-7","article-title":"Filamentous \u03b1-synuclein inclusions link multiple system atrophy with Parkinson\u2019s disease and dementia with Lewy bodies","volume":"251","author":"Spillantini","year":"1998","journal-title":"Neurosci. Lett."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/PL00007400","article-title":"NACP\/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson\u2019s disease brains","volume":"99","author":"Wakabayashi","year":"2000","journal-title":"Acta Neuropathol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0014-5793(98)01146-6","article-title":"Synthetic filaments assembled from C-terminally truncated \u03b1-synuclein","volume":"436","author":"Crowther","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0896-6273(02)00682-7","article-title":"Neuronal \u03b1-synucleinopathy with severe movement disorder in mice expressing A53T human \u03b1-synuclein","volume":"34","author":"Giasson","year":"2002","journal-title":"Neuron"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1016\/j.neurobiolaging.2011.06.022","article-title":"Prion-like acceleration of a synucleinopathy in a transgenic mouse model","volume":"33","author":"Mougenot","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1126\/science.1227157","article-title":"Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice","volume":"338","author":"Luk","year":"2012","journal-title":"Science"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"E5308","DOI":"10.1073\/pnas.1514475112","article-title":"Evidence for \u03b1-synuclein prions causing multiple system atrophy in humans with parkinsonism","volume":"112","author":"Prusiner","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"10732","DOI":"10.1073\/pnas.1321785111","article-title":"Intramuscular injection of \u03b1-synuclein induces CNS \u03b1-synuclein pathology and a rapid-onset motor phenotype in transgenic mice","volume":"111","author":"Sacino","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Ayers, J.I., Brooks, M.M., Rutherford, N.J., Howard, J.K., Sorrentino, Z.A., Riffe, C.J., and Giasson, B.I. (2017). Robust central nervous system pathology in transgenic mice following peripheral injection of \u03b1-synuclein fibrils. J. Virol., 91.","DOI":"10.1128\/JVI.02095-16"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00401-017-1762-2","article-title":"MSA prions exhibit remarkable stability and resistance to inactivation","volume":"135","author":"Woerman","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1056\/NEJMoa1812840","article-title":"Randomized trial of verubecestat for prodromal Alzheimer\u2019s disease","volume":"380","author":"Egan","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.biopsych.2017.08.010","article-title":"Anti-amyloid-\u03b2 monoclonal antibodies for Alzheimer\u2019s disease: Pitfalls and promise","volume":"83","year":"2018","journal-title":"Biol. Psychiatry"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4861\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:57:04Z","timestamp":1760162224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4861"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":140,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22094861"],"URL":"https:\/\/doi.org\/10.3390\/ijms22094861","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]}}}