APOE Genotype Impacts Polyunsaturated Neutral Lipid Storage and Ferroptosis Vulnerability in Astrocytes.

Astrocytes play a critical role in regulating the metabolism of cholesterol and other lipids in the brain. Increasing evidence suggests that dysfunctional lipid metabolism and lipid peroxide-mediated cell death, or ferroptosis, are involved in the pathophysiology of late-onset Alzheimer’s disease. The Alzheimer’s disease risk allele of APOE, APOE4, is expressed in astrocytes and is associated with increased accumulation of cholesterol as well as highly polyunsaturated and peroxidation-prone neutral lipids in lipid droplets. However, a direct connection between APOE4 genotype-dependent lipid dysregulation and sensitivity to ferroptotic cell death has not yet been explored. Here, we show that APOE4 and APOE knockout astrocytes accumulate cholesterol and polyunsaturated lipid-rich droplets in lysosomes and have increased vulnerability to ferroptotic cell death. APOE2 astrocytes are also enriched in polyunsaturated lipids but are less vulnerable to lipid peroxidation. Pharmacological manipulation of neutral lipid content modestly impacted ferroptosis sensitivity. In contrast, modulation of lysosomal lipid content via blockade of autophagy or promotion of cholesterol efflux with methyl-β-cyclodextrin strongly protects APOE4 cells from lipid-peroxide mediated cell death. In humanized APOE4 mice, reduction of brain lipid peroxidation selectively impacted cholesterol ester storage. Taken together, these findings suggest that correction of APOE4-mediated lipid trafficking defects may reduce risk for ferroptotic in astrocytes.