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Here using human iPSC-derived cerebral organoid models, we find that <jats:italic>APOE<\/jats:italic> deletion increases \u03b1-synuclein (\u03b1Syn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, <jats:italic>APOE4<\/jats:italic> cerebral organoids have increased \u03b1Syn accumulation compared to those with <jats:italic>APOE3<\/jats:italic>. Carrying <jats:italic>APOE4<\/jats:italic> also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and \u03b1Syn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how <jats:italic>APOE4<\/jats:italic> drives the risk for synucleinopathies.<\/jats:p>","DOI":"10.1007\/s00401-021-02361-9","type":"journal-article","created":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T06:02:23Z","timestamp":1630130543000},"page":"807-825","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Apolipoprotein E regulates lipid metabolism and \u03b1-synuclein pathology in human iPSC-derived cerebral organoids"],"prefix":"10.1007","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4520-6307","authenticated-orcid":false,"given":"Jing","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxue","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka A.","family":"Martens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Shue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary D.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuyao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Chen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neill R.","family":"Graff-Radford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbigniew K.","family":"Wszolek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven G.","family":"Younkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Brafman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nil\u00fcfer","family":"Ertekin-Taner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan W.","family":"Asmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziying","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixia","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianlin","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahisa","family":"Kanekiyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3491-1016","authenticated-orcid":false,"given":"Guojun","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,28]]},"reference":[{"key":"2361_CR1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12068","author":"Alzheimer's Association","year":"2020","unstructured":"Alzheimer\u2019s Association (2020) 2020 Alzheimer\u2019s disease facts and figures. 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