APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size

Author:

Windham Ian A.,Ragusa Joey V.,Wallace E. Diane,Wagner Colby H.,White Kristen K.,Cohen SarahORCID

Abstract

AbstractTheE4variant ofAPOEstrongly predisposes individuals to late-onset Alzheimer’s disease. We demonstrate that in response to neutral lipid synthesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the ER lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts.APOEknockdown promotes fewer, larger LDs containing more unsaturated triglyceride. This LD size distribution phenotype was rescued by chimeric APOE that targets only LDs. APOE4-expressing astrocytes also form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the larger LDs inAPOE4cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition.APOE4is a toxic gain of function variant that causes aberrant LD composition and morphology. We propose thatAPOE4astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation or lipotoxicity, which could contribute to Alzheimer’s disease risk.SummaryWindhamet al. discover that APOE in astrocytes can traffic to lipid droplets (LDs), where it modulates LD composition and size. Astrocytes expressing the Alzheimer’s risk variant APOE4 form large LDs with impaired turnover and increased peroxidation sensitivity.

Publisher

Cold Spring Harbor Laboratory

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Cell type-specific roles of APOE4 in Alzheimer disease;Nature Reviews Neuroscience;2024-01-08

2. The cell biology of APOE in the brain;Trends in Cell Biology;2023-10

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