{"id":"https://openalex.org/G5895166375","display_name":"Apolipoprotein E4 Alters Cerebral Lipid Metabolism","description":"The apolipoprotein E gene is a strong genetic predictor for vascular dementia and carries significant risk for cardiovascular disease. In humans, there are three major isoforms of apolipoprotein E (apoE): E2, E3, and E4. E4 confers between a 2 (heterozygous) to 15 fold (homozygous) increase in risk of late onset Alzheimer's disease compared to E3. ApoE is primarily secreted by astrocytes and serves as the main lipid carrier in the brain. Lipid uptake and metabolism in astrocytes therefore relies on apoE. While apoE regulation of lipid metabolism is well known in the periphery, a gap in the field exists as to apoE's role in CNS lipid metabolism. In this study we characterize an increase in lipid droplet (LD) formation in astrocytes expressing human E4. Compared to E3 expressing astrocytes, E4 astrocytes exhibit significantly greater numbers of LDs. Additionally, E4 astrocytes exhibited more LDs than E3 astrocytes at varying concentrations of oleic acid supplementation. Metabolic studies were conducted to measure uptake and oxidation of fatty acids (14C palmitate) in astrocytes. It was found that E4 astrocytes take up palmitate at a higher rate than E3 astrocytes, and furthermore oxidize less palmitate compared to E3. This data suggests a mismanagement of lipid homeostasis in the E4 brain and provides the justification for the current proposal. In order to dissect the apoE contributions to lipid uptake in astrocytes, we will use pharmacologic and genetic inhibitors of LDLR and fatty acid transporters and measure intracellular lipid storage. Secondly, we will study how apoE modulates lipid oxidation by tracing labeled palmitate to its labeled byproducts. Thirdly, we will translate our findings to human tissue by correlating AD and vascular dementia pathology, APOE genotype, and clinical symptoms with LD presence in astrocytes and vascular endothelium. Completion of this proposal will be a breakthrough in our understanding of apoE's role in cerebral lipid metabolism. Determining the mechanisms contributing to LD formation in E4 glia could offer insights into potential therapies to mitigate disease risk.","funder_award_id":"19PRE34380094","funder":{"id":"https://openalex.org/F4320306230","display_name":"American Heart Association","doi":"10.13039/100000968"},"funded_outputs":["https://openalex.org/W2917914009","https://openalex.org/W3045446366"],"funded_outputs_count":2,"parent_awards":[],"sub_awards":[],"sub_awards_count":0,"amount":53688.0,"currency":"USD","amount_usd":53688.0,"amount_usd_basis":"usd_native","recipients":[],"recipient_countries":[],"recipient_regions":[],"research_scope":{"is_research":true,"basis":"funder_default","tier":1},"funding_type":"training","funder_scheme":"Predoctoral Fellowship","start_date":"2019-01-01","end_date":"2019-09-28","start_year":2019,"end_year":2019,"landing_page_url":"https://professional.heart.org/en/research-programs/aha-funded-research","doi":null,"provenance":"aha_report_builder","lead_investigator":{"given_name":"Brandon","family_name":"Farmer","orcid":null,"role_start":null,"affiliation":{"name":"University of Kentucky, Lexington","country":"US","ids":null}},"co_lead_investigator":null,"investigators":[{"given_name":"Brandon","family_name":"Farmer","orcid":null,"role_start":null,"affiliation":{"name":"University of Kentucky, Lexington","country":"US","ids":null}}],"works_api_url":"https://api.openalex.org/works?filter=awards.id:G5895166375","primary_topic":null,"topics":null,"institution_awarded":[{"id":"https://openalex.org/I143302722","display_name":"University of Kentucky","ror":"https://ror.org/02k3smh20","country_code":"US","type":"education","lineage":["https://openalex.org/I143302722"]}],"updated_date":"2026-10-16T03:01:01.000Z","created_date":"2026-07-13T04:53:37.000Z"}