Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity

Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer’s disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer’s disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells. [Display omitted] •Microglia-like cells (iMGLs) respond to soluble factors secreted by neurons•APOE4 renders iMGLs weakly responsive to neuronal activity•APOE4 iMGLs disrupts the coordinated activity of neuronal ensembles•Microglial lipid homeostasis is critical to sustain surveillance states Tsai and colleagues explored the impact of the Alzheimer’s disease-associated risk gene APOE4 onto the cellular communication of neurons and microglia. Through combinatorial experiments with cells derived from CRISPR-edited APOE isogenic lines, this work defines the functional consequence of impaired microglial lipid metabolism induced by APOE4 onto neuronal network activity.