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

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