ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer’s disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation. [Display omitted] •Human ApoE4 astrocytes display increased glycolytic activity and reduced OXPHOS•ApoE4 induces defective autophagy and mitochondrial dysfunction in human astrocytes•Mitigating cholesterol burden restores mitochondrial respiration in ApoE4 astrocytes Lee et al. identify ApoE4-dependent mitochondrial dysfunction in human astrocytes and its underlying mechanisms. This study suggests the detrimental effects of ApoE4 on brain metabolism, especially in the later stages of life when the brain greatly depends on oxidative respiration for its function.