Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease.

APOE and Trem2 are major genetic risk factors for Alzheimer's disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate Aβ uptake, and ameliorate Aβ effects on cognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, cortical infusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an activated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack of TREM2 decreases Aβ uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to Aβ mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD.