GSE158962
Phospholipid composition of APOE lipoproteins affects microglia activation in an isoform-specific manner
Apolipoprotein E4 (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). Our lipidomic analysis identified a common phospholipid signature with a high level of correlation between APOEe3/3 and APOEe4/4 AD postmortem brain samples and native lipoproteins isolated from astrocyte conditioned media of mice expressing human APOE3 or APOE4. Behavioral testing demonstrated that native E3 lipoproteins were more effective than E4 at ameliorating the harmful effects of Aß on cognition. We posit that APOE isoform-specific differences in the phospholipid composition of native lipoproteins prompt a differential microglial response. Using time-lapse in vivo two-photon imaging, we compared the effect of E3 or E4 infused with Aß and determined that E3 lipoproteins induced a faster microglial migration towards Aß. To determine how E3 and E4 lipoproteins affect microglial transcriptome in response to Aß, we performed bulk and single cell RNA-seq of WT and Trem2ko mice. We show that compared to E4, cortical infusion of E3 lipoproteins upregulated a higher proportion of genes associated with an activated immune response accompanied by a downregulation of homeostatic genes. scRNA-seq identified microglia-specific clusters affected by Trem2 deficiency, suggesting that lack of Trem2 impairs the transition of microglia from homeostatic to an activated state. Compared to E3, E4-expressing microglia showed a reduced Aß uptake that was additionally aggravated by Trem2 deficiency. Together, our findings have elucidated unique phenotypic and transcriptional differences in the microglial response to Aß in the presence of E3 or E4 lipoproteins which could impact AD pathogenesis. Overall design: Isolated microglia and neuron from wild-type C57BL/6J, 129P2(Cg)-Cx3cr1tm1Litt/J (Cx3cr1GFP) and Trem2em2ADiuj/J mice (Trem2ko) were used to reveal transcriptomic changes in response to Aß injection using bulk and single cell RNA-seq.