Clearance of intracellular lipids by lipophagy impaired in APOE ε4 human astrocytes

Abstract

AbstractBackgroundApolipoprotein E (APOE) ɛ4 is the strongest known genetic risk factor for Alzheimer’s disease. APOE ɛ4 has been found to impair lipid metabolism in human glia causing accumulation of intracellular lipid droplets. We hypothesized that this phenotype in human APOE ɛ4/ɛ4 astrocytes was due to defective clearance via lipophagy.MethodGlobal transcriptomic analyses were performed on astrocytes derived from isogenic and population model human induced pluripotent stem cells (iPSCs). Fluorescent reporters, immunocytochemistry, and western blotting were used to quantify lipid droplets and autophagic machinery in iPSC‐based models.ResultGlobal transcriptomic analyses reveal that APOE ε4 drives autophagy dysregulation in astrocytes from human iPSCs. High‐content imaging of fluorescent autophagy reporters and immunocytochemistry revealed accumulation of lipid droplets and autophagy machinery in APOE ɛ4/ɛ4 astrocytes which was ameliorated by induction of autophagy.ConclusionHuman iPSC‐derived APOE ɛ4/ɛ4 astrocytes exhibit impaired lipophagy.