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Converging evidence indicates that the intracellular transmission and subsequent templated amplification of \u03b1\u2010syn are involved in the onset and progression of PD. However, the molecular mechanisms underlying the cell\u2010to\u2010cell transmission of pathological \u03b1\u2010syn remain poorly understood. Microglia is highly activated in the brains of PD patients. Here, it is shown that depletion of microglia slows the spread of pathological \u03b1\u2010syn pathology in mice injected with \u03b1\u2010syn fibrils. Microglia phagocytose \u03b1\u2010syn fibrils and transform them into more toxic species. The phagocytosis of \u03b1\u2010syn fibrils by microglia is partially mediated by triggering a receptor expressed on myeloid cells 2 (TREM2), a transmembrane protein expressed on the surface of microglia. The endocytosed \u03b1\u2010syn fibrils are then cleaved by the lysosomal proteinase asparagine endopeptidase (AEP) to generate truncated \u03b1\u2010syn 1\u2013103 fibrils with enhanced seeding activity. Knockout of TREM2 and AEP impedes the endocytosis and cleavage of \u03b1\u2010syn fibrils, respectively. The results demonstrate that TREM2\u2010mediated phagocytosis of \u03b1\u2010syn fibrils by microglia and subsequent AEP\u2010mediated cleavage of \u03b1\u2010syn fibrils contribute to the spread of \u03b1\u2010syn in the brain. Blocking either of these two steps attenuates the progression of \u03b1\u2010syn pathology.<\/jats:p>","DOI":"10.1002\/advs.202413451","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T05:48:24Z","timestamp":1733982504000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Microglia Process \u03b1\u2010Synuclein Fibrils and Enhance their Pathogenicity in a TREM2\u2010Dependent Manner"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8669-4239","authenticated-orcid":false,"given":"Min","family":"Xiong","sequence":"first","affiliation":[{"name":"Department of Neurology Renmin Hospital of Wuhan University  Wuhan 430060 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danhao","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Neurology Renmin Hospital of Wuhan University  Wuhan 430060 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