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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,8,23]]},"abstract":"<jats:p>\n                    Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer\u2019s disease (AD). Apolipoprotein E4 (\n                    <jats:italic>APOE4<\/jats:italic>\n                    ), the highest genetic risk factor for late-onset AD, has been shown to exacerbate tau hyperphosphorylation in mouse models. However, the exact mechanisms through which APOE4 induces tau hyperphosphorylation remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), which we identify as a binding partner of APOE4, drives tau hyperphosphorylation. We discovered that first, GPC-4 preferentially interacts with APOE4 in comparison to APOE2, considered to be a protective allele to AD, and second, that postmortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. Furthermore, the astrocyte-secreted GPC-4 induced both tau accumulation and propagation in\u00a0vitro. CRISPR\/dCas9-mediated activation of GPC-4 in a tauopathy mouse model robustly induced tau hyperphosphorylation. In the absence of GPC4, APOE4-induced tau hyperphosphorylation was largely diminished using in\u00a0vitro tau fluorescence resonance energy transfer-biosensor cells, in human-induced pluripotent stem cell-derived astrocytes and in an in\u00a0vivo mouse model. We further show that APOE4-mediated surface trafficking of APOE receptor low-density lipoprotein receptor-related protein 1 through GPC-4 can be a gateway to tau spreading. Collectively, these data support that APOE4-induced tau hyperphosphorylation is directly mediated by GPC-4.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2108870119","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T15:21:26Z","timestamp":1660576886000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":76,"title":["Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0818-9966","authenticated-orcid":false,"given":"Sivaprakasam R.","family":"Saroja","sequence":"first","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine, Mount Sinai, New York, NY 10029"},{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirill","family":"Gorbachev","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine, Mount Sinai, New York, NY 10029"},{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TCW","family":"Julia","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0576-2472","authenticated-orcid":false,"given":"Alison M.","family":"Goate","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana C.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine, Mount Sinai, New York, NY 10029"},{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Ronald M. 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