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More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to \u03b1-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact \u03b1-synuclein pathology has not been well delineated. We report here that when treated with human \u03b1-synuclein preformed fibrils, exosomes containing \u03b1-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced \u03b1-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from \u03b1-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated \u03b1-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of \u03b1-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that \u03b1-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia\/macrophage derived exosomes in the CSF of Parkinson\u2019s disease patients, we confirmed the presence of \u03b1-synuclein oligomer in CD11b+ exosomes, which were able to induce \u03b1-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of \u03b1-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awaa090","type":"journal-article","created":{"date-parts":[[2020,3,15]],"date-time":"2020-03-15T20:25:11Z","timestamp":1584303911000},"page":"1476-1497","source":"Crossref","is-referenced-by-count":532,"title":["Microglial exosomes facilitate \u03b1-synuclein transmission in Parkinson\u2019s disease"],"prefix":"10.1093","volume":"143","author":[{"given":"Min","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Neurology, Huashan hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology, Huashan hospital, Fudan University, Shanghai, China"},{"name":"Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxin","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Neurology, The 10th People\u2019s Hospital, Tongji University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Neurology, Huashan hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sida","family":"Han","sequence":"first","affiliation":[{"name":"Department of Neurology, Huashan hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Neurology, Huashan hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Tieu","sequence":"first","affiliation":[{"name":"Department of Environmental Health Sciences, Florida International University, Miami, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,1]]},"reference":[{"key":"2020052115181840400_awaa090-B1","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1126\/science.1227901","article-title":"Microglia: scapegoat, saboteur, or something else?","volume":"339","author":"Aguzzi","year":"2013","journal-title":"Science"},{"key":"2020052115181840400_awaa090-B2","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.nbd.2011.01.029","article-title":"Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission","volume":"42","author":"Alvarez-Erviti","year":"2011","journal-title":"Neurobiol Dis"},{"key":"2020052115181840400_awaa090-B3","first-page":"25","article-title":"Apoptosis and autophagy in nigral neurons of patients with Parkinson\u2019s disease","volume":"12","author":"Anglade","year":"1997","journal-title":"Histol Histopathol"},{"key":"2020052115181840400_awaa090-B4","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/nn.4132","article-title":"Depletion of microglia and inhibition of exosome synthesis halt tau propagation","volume":"18","author":"Asai","year":"2015","journal-title":"Nat Neurosci"},{"key":"2020052115181840400_awaa090-B5","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3389\/fimmu.2014.00403","article-title":"Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness","volume":"5","author":"Baixauli","year":"2014","journal-title":"Front Immunol"},{"key":"2020052115181840400_awaa090-B6","doi-asserted-by":"crossref","first-page":"21883","DOI":"10.1074\/jbc.273.34.21883","article-title":"Isolation and characterization of rat liver amphisomes. 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