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

Abstract

The E4 variant of APOE strongly 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. APOE knockdown 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 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 is a toxic gain of function variant that causes aberrant LD composition and morphology. We propose that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation or lipotoxicity, which could contribute to Alzheimer's disease risk.

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders

“…Some mechanistic studies show that ApoE4 directly dysregulates the cholesterol pathway in different cell types, which further impairs myelination of oligodendrocytes [112], induces malfunction of astrocytes and microglia [113][114][115], and promotes pathogenesis of AD [111,116,117]. ApoE4 also affects sphingolipid metabolism [118] and LD storage [115,116,[119][120][121][122] to facilitate AD progression. ApoJ, besides its direct involvement in lipid transport and metabolism, can bind to Aβ oligomers and interfere with Aβ aggregation, which further induces neurotoxicity with excess amounts of Aβ [123].…”

Triglyceride metabolism controls inflammation andAPOE4-associated disease states in microglia

“…This has now been observed in multiple other systems including neuron-microglial co-cultures 23,24 , post-mortem brain samples 24,28 , and mouse models 17,27,29 . Recent reports even suggest that APOE functions as a lipid-droplet binding protein 30 .…”