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We found, by examining cells stably expressing each APOE isoform, that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-Golgi compartment is degraded through autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells, and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that might contribute to AD pathogenesis.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/jcs.258687","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T14:12:42Z","timestamp":1641305562000},"source":"Crossref","is-referenced-by-count":34,"title":["Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins"],"prefix":"10.1242","volume":"135","author":[{"given":"Gianna M.","family":"Fote","sequence":"first","affiliation":[{"name":"UC Irvine Department of Biological Chemistry 1 , 825 Health Sciences Road, Medical Sciences I, Room D240, UC Irvine School of Medicine, Irvine, CA 92697-1700 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolette R.","family":"Geller","sequence":"additional","affiliation":[{"name":"UC Irvine Department of Psychiatry and Human Behavior 2 , Neuropsychiatric Center, UC Irvine Medical Center, 101 The City Drive South, Building 3, Route 88, Orange, CA 92868 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos E.","family":"Efstathiou","sequence":"additional","affiliation":[{"name":"Harvard Medical School Department of Ophthalmology 3 , 243 Charles Street, Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Hendricks","sequence":"additional","affiliation":[{"name":"Institute for Integrative Genome Biology, UC Riverside 4 , Eucalyptus Drive, Riverside, CA 92521 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demetrios G.","family":"Vavvas","sequence":"additional","affiliation":[{"name":"Harvard Medical School Department of Ophthalmology 3 , 243 Charles Street, Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack C.","family":"Reidling","sequence":"additional","affiliation":[{"name":"UC Irvine MIND Institute 5 , 2642 Biological Sciences III, Irvine, CA 92697-4545 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie M.","family":"Thompson","sequence":"additional","affiliation":[{"name":"UC Irvine Department of Biological Chemistry 1 , 825 Health Sciences Road, Medical Sciences I, Room D240, UC Irvine School of Medicine, Irvine, CA 92697-1700 , USA"},{"name":"UC Irvine Department of Psychiatry and Human Behavior 2 , Neuropsychiatric Center, UC Irvine Medical Center, 101 The City Drive South, Building 3, Route 88, Orange, CA 92868 , USA"},{"name":"UC Irvine MIND Institute 5 , 2642 Biological Sciences III, Irvine, CA 92697-4545 , USA"},{"name":"UC Irvine Department of Neurobiology and Behavior 6 , 2205 McGaugh Hall, Irvine, CA 92697 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2467-6294","authenticated-orcid":false,"given":"Joan S.","family":"Steffan","sequence":"additional","affiliation":[{"name":"UC Irvine Department of Psychiatry and Human Behavior 2 , Neuropsychiatric Center, UC Irvine Medical Center, 101 The City Drive South, Building 3, Route 88, Orange, CA 92868 , USA"},{"name":"UC Irvine MIND Institute 5 , 2642 Biological Sciences III, Irvine, CA 92697-4545 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2022,1,25]]},"reference":[{"key":"2024061307271974300_JCS258687C1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.3390\/genes10030222","article-title":"The genetic variability of APOE in different human populations and its implications for longevity","volume":"10","author":"Abondio","year":"2019","journal-title":"Genes (Basel)"},{"key":"2024061307271974300_JCS258687C2","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1126\/science.aan6298","article-title":"Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes","volume":"358","author":"Abu-Remaileh","year":"2017","journal-title":"Science (80-.)"},{"key":"2024061307271974300_JCS258687C3","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.bbalip.2017.11.006","article-title":"Cell culture models of fatty acid overload: Problems and solutions","volume":"1863","author":"Alsabeeh","year":"2018","journal-title":"Biochim. 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