<i>APOE4</i> disrupts intracellular lipid homeostasis in human iPSC-derived glia.

Abstract

The <i>E4</i> allele of the apolipoprotein E gene (<i>APOE</i>) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer's disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. However, it is unclear how APOE4 perturbs the intracellular lipid state. Here, we report that <i>APOE4</i>, but not <i>APOE3</i>, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)-derived astrocytes generated from fibroblasts of <i>APOE4</i> or <i>APOE3</i> carriers, and of yeast expressing human <i>APOE</i> isoforms. We combined lipidomics and unbiased genome-wide screens in yeast with functional and genetic characterization to demonstrate that human APOE4 induced altered lipid homeostasis. These changes resulted in increased unsaturation of fatty acids and accumulation of intracellular lipid droplets both in yeast and in <i>APOE4</i>-expressing human iPSC-derived astrocytes. We then identified genetic and chemical modulators of this lipid disruption. We showed that supplementation of the culture medium with choline (a soluble phospholipid precursor) restored the cellular lipidome to its basal state in <i>APOE4</i>-expressing human iPSC-derived astrocytes and in yeast expressing human <i>APOE4</i> Our study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the <i>APOE4</i> genotype. Our study suggests that manipulating lipid metabolism could be a therapeutic approach to help alleviate the consequences of carrying the <i>APOE4</i> allele.