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The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to lipogenesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the endoplasmic reticulum (ER) lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs after a fatty acid pulse, which contain more unsaturated triglyceride after fatty acid pulse-chase. This LD size phenotype was rescued by chimeric APOE that targets only LDs. Like APOE depletion, APOE4-expressing astrocytes form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the LDs in APOE4 cells 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. APOE4 causes aberrant LD composition and morphology. Our study contributes to accumulating evidence that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation, which could contribute to Alzheimer's disease risk., (© 2024 Windham et al.)

Lipid droplets (LDs) are key organelles for fat storage and trafficking. In this issue, Rogers et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202205053) show that glucose restriction triggers liquid crystalline lattice formation within LDs, which in turn alters the recruitment of proteins to the LD surface., (© 2022 Windham and Cohen.)

Apolipoprotein E (APOE) mediates multiple aspects of brain lipid homeostasis in both physiological and pathological contexts. Evidence points to defects in metabolism, intracellular trafficking, and innate immune pathways, particularly in glial cells, underlying the pathogenic effects of the APOE4 variant in Alzheimer's disease. Understanding how E4 predisposes individuals to disease requires a deeper mechanistic understanding of the trafficking mechanisms of APOE within and between cells in the brain. Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes. [ABSTRACT FROM AUTHOR]