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As reports suggest a link between BIN1, Tau and extracellular vesicles, we investigated whether BIN1 could affect Tau spreading via exosomes secretion. We observed that BIN1-associated Tau-containing extracellular vesicles purified from cerebrospinal fluid of AD-affected individuals are seeding-competent. We showed that BIN1 over-expression promotes the release of Tau via extracellular vesicles\n                    <jats:italic>in vitro<\/jats:italic>\n                    as well as exacerbation of Tau pathology\n                    <jats:italic>in vivo<\/jats:italic>\n                    in PS19 mice. Genetic deletion of\n                    <jats:italic>Bin1<\/jats:italic>\n                    from microglia resulted in reduction of Tau secretion via extracellular vesicles\n                    <jats:italic>in vitro<\/jats:italic>\n                    , and in decrease of Tau spreading\n                    <jats:italic>in vivo<\/jats:italic>\n                    in male, but not female, mice, in the context of PS19 background. Interestingly, ablation of Bin1 in microglia of male mice resulted in significant reduction in the expression of heat-shock proteins, previously implicated in Tau proteostasis. These observations suggest that BIN1 could contribute to the progression of AD-related Tau pathology by altering Tau clearance and promoting release of Tau-enriched extracellular vesicles by microglia.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-45676-0","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T06:02:54Z","timestamp":1561960974000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":172,"title":["BIN1 favors the spreading of Tau via extracellular vesicles"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9421-4370","authenticated-orcid":false,"given":"Andrea","family":"Crotti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hameetha Rajamohamend","family":"Sait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"McAvoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karol","family":"Estrada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayla","family":"Ergun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Szak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Marsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Jandreski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor L.","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isin","family":"Dalkilic-Liddle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Cameron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Cahir-McFarland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0175-6910","authenticated-orcid":false,"given":"Richard M.","family":"Ransohoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,7,1]]},"reference":[{"key":"45676_CR1","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","volume":"82","author":"H Braak","year":"1991","unstructured":"Braak, H. & Braak, E. 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All the authors of the manuscript, with the exception of A.C., R.M.R., K.M.M., A.E., K.E., and N.B.B., are employees of Biogen. A.C., K.E., A.E., K.M.M. and R.M.R. are former of Biogen employees. A.C. is an employee of Astellas. K.E. is an employee of BioMarin. A.E. is an employee of Fulcrum Therapeutics. R.M.R. is an employee of Third Rock Venture Capital. The authors declare no non- financial competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"9477"}}