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It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the \u03b54 allele of\n                    <jats:italic>APOE<\/jats:italic>\n                    is the highest genetic risk factor for developing late-onset Alzheimer\u2019s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the\n                    <jats:italic>APOE4<\/jats:italic>\n                    allele.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-97117-6","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T10:32:14Z","timestamp":1632393134000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["ApoE4 attenuates autophagy via FoxO3a repression in the brain"],"prefix":"10.1038","volume":"11","author":[{"given":"Hee-Young","family":"Sohn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Ik","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jee-Yun","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Hye","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Ho","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chulman","family":"Jo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,2]]},"reference":[{"key":"97117_CR1","doi-asserted-by":"publisher","first-page":"a0006312","DOI":"10.1101\/cshperspect.a006312","volume":"2","author":"DM Holtzman","year":"2012","unstructured":"Holtzman, D. 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