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 A beta remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOE epsilon 3/3 and APOE epsilon 4/4 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 A beta, facilitate A beta uptake, and ameliorate A beta 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 A beta uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to A beta mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD. Microglia can clear amyloid plaques in Alzheimer's disease. Here, the authors show that specific isoforms of the phospholipid forming APOE lipoproteins activate microglia in pre-clinical mouse models of Alzheimer's disease.

Automated summary

The study demonstrates that different isoforms of the APOE lipoproteins activate microglia in pre-clinical mouse models of Alzheimer's disease, affecting their response to A beta.