Isoform‐ and cellular metabolism‐specific apolipoprotein E (ApoE) lipidation in astrocytes

Abstract

AbstractBackgroundApolipoprotein E (ApoE) is the major lipoprotein in the brain and connects the metabolic interactions between astrocytes and neurons. The E4 variant (APOE4) affects this function and represents a genetic predisposition for Alzheimer’s disease (AD), but the molecular mechanisms remain unclear.MethodWe have integrated cell‐free in vitro assays, a new cell system based on isogenic iPSC‐derived astrocytes and lipidomics to study ApoE lipidation, and how this is affected by genetic polymorphism.ResultWe show that ApoE produces different types of lipoprotein particles via distinct lipidation pathways. ApoE forms high‐density lipoprotein (HDL)‐like, cholesterol‐rich particles via the ATP‐binding cassette transporter 1 (ABCA1), a mechanism largely unaffected by ApoE polymorphism. Alternatively, ectopic accumulation of fat in astrocytes, a stress‐associated condition, redirects ApoE toward the assembly and secretion of triacylglycerol‐rich lipoprotein particles, a process boosted by the APOE4 variant. We demonstrate in vitro that ApoE can detect triacylglycerol in membranes and spontaneously assemble lipoprotein particles (10‐20 nm) rich in unsaturated triacylglycerol, and that APOE4 has remarkable properties behaving as a strong triacylglycerol binder. Fatty APOE4 astrocytes have reduced ability to clear toxic fatty acids from the extracellular milieu, because APOE4 reroutes them back to secretion.ConclusionThe molecular mechanisms discussed here provide a new model explaining the interaction between genetic polymorphism and environmental factors, such as dyslipidaemia or aging, in the aetiology of late‐onset AD, as well as inspire possible new strategies for therapeutic intervention.Graphical abstract from https://doi.org/10.1016/j.celrep.2022.110435.