{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:03:48Z","timestamp":1792789428608,"version":"4.5.0"},"reference-count":88,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T00:00:00Z","timestamp":1729814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH)","award":["AG065992"],"award-info":[{"award-number":["AG065992"]}]},{"name":"National Institutes of Health (NIH)","award":["AG068550"],"award-info":[{"award-number":["AG068550"]}]},{"name":"National Institutes of Health (NIH)","award":["3123226"],"award-info":[{"award-number":["3123226"]}]},{"name":"National Institutes of Health (NIH)","award":["3123227"],"award-info":[{"award-number":["3123227"]}]},{"name":"UAB Startup","award":["AG065992"],"award-info":[{"award-number":["AG065992"]}]},{"name":"UAB Startup","award":["AG068550"],"award-info":[{"award-number":["AG068550"]}]},{"name":"UAB Startup","award":["3123226"],"award-info":[{"award-number":["3123226"]}]},{"name":"UAB Startup","award":["3123227"],"award-info":[{"award-number":["3123227"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer\u2019s disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-\u03b53 (ApoE3) alleles, while ApoE-\u03b52 (ApoE2) is protective from AD, and ApoE-\u03b54 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE\u2019s role in lipid metabolism is also not fully known. Lipid droplets increase in AD. However, how ApoE contributes to lipid accumulation in the brain remains unknown. Methods: Here, we use Drosophila to study the effects of ApoE alleles on lipid accumulation in the brain and muscle in a cell-autonomous and non-cell-autonomous manner. Results: We report that pan-neuronal expression of each ApoE allele induces lipid accumulation specifically in the brain, but not in the muscle. However, this was not the case when expressed with muscle-specific drivers. ApoE2- and ApoE3-induced lipid accumulation is dependent on the expression of Dgat2, a key regulator of triacylglycerol production, while ApoE4 still induces lipid accumulation even with knock-down of Dgat2. Additionally, we find that implementation of time-restricted feeding (TRF), a dietary intervention in which food access only occurs in the active period (day), prevents ApoE-induced lipid accumulation in the brain of flies and modulates lipid metabolism genes. Conclusions: Altogether, our results demonstrate that ApoE induces lipid accumulation in the brain, that ApoE4 is unique in causing lipid accumulation independent of Dgat2, and that TRF prevents ApoE-induced lipid accumulation. These results support the idea that lipid metabolism is critical in AD, and that TRF could be a promising therapeutic approach to prevent ApoE-associated dysfunction in lipid metabolism.<\/jats:p>","DOI":"10.3390\/genes15111376","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T07:51:29Z","timestamp":1729842689000},"page":"1376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Apolipoprotein E Induces Lipid Accumulation Through Dgat2 That Is Prevented with Time-Restricted Feeding in Drosophila"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0178-8480","authenticated-orcid":false,"given":"Ruan C. M.","family":"Moraes","sequence":"first","affiliation":[{"name":"Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8978-4507","authenticated-orcid":false,"given":"Jonathan R.","family":"Roth","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"Department of Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savannah R.","family":"Crawley","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittney P.","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0353-4633","authenticated-orcid":false,"given":"Girish C.","family":"Melkani","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"},{"name":"UAB Nathan Shock Center, 1300 University Boulevard, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Collaborators","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0006-8993(96)01448-5","article-title":"Severe learning deficits in apolipoprotein E-knockout mice in a water maze task","volume":"752","author":"Oitzl","year":"1997","journal-title":"Brain Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbr.2004.09.019","article-title":"Human apoE targeted replacement mouse lines: H-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior","volume":"159","author":"Grootendorst","year":"2005","journal-title":"Behav. 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