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Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase C\u03b6 (aPKC\u03b6) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin\u2013Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.<\/jats:p>","DOI":"10.1242\/jcs.180745","type":"journal-article","created":{"date-parts":[[2016,4,5]],"date-time":"2016-04-05T01:11:26Z","timestamp":1459818686000},"page":"2003-2015","source":"Crossref","is-referenced-by-count":38,"title":["FRMD4A\u2013cytohesin signaling modulates the cellular release of tau"],"prefix":"10.1242","volume":"129","author":[{"given":"Xu","family":"Yan","sequence":"first","affiliation":[{"name":"Neuroscience Center, University of Helsinki, FI-00014 Helsinki 1 , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niko-Petteri","family":"Nyk\u00e4nen","sequence":"additional","affiliation":[{"name":"Neuroscience Center, University of Helsinki, FI-00014 Helsinki 1 , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia A.","family":"Brunello","sequence":"additional","affiliation":[{"name":"Neuroscience Center, University of Helsinki, FI-00014 Helsinki 1 , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annakaisa","family":"Haapasalo","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine-Neurology, University of Eastern Finland 2 , FI-70211 Kuopio , Finland"},{"name":"Kuopio University Hospital, FI-70029 3 Department of Neurology , \u2008 Kuopio , Finland"},{"name":"Institute of Biomedicine, University of Eastern Finland 4 , FI-70211 Kuopio , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko","family":"Hiltunen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine-Neurology, University of Eastern Finland 2 , FI-70211 Kuopio , Finland"},{"name":"Kuopio University Hospital, FI-70029 3 Department of Neurology , \u2008 Kuopio , Finland"},{"name":"Institute of Biomedicine, University of Eastern Finland 4 , FI-70211 Kuopio , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riikka-Liisa","family":"Uronen","sequence":"additional","affiliation":[{"name":"Neuroscience Center, University of Helsinki, FI-00014 Helsinki 1 , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9867-4438","authenticated-orcid":false,"given":"Henri J.","family":"Huttunen","sequence":"additional","affiliation":[{"name":"Neuroscience Center, University of Helsinki, FI-00014 Helsinki 1 , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2024061315580589600_JCS180745C1","doi-asserted-by":"publisher","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. 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