Complement C3aR depletion reverses HIF-1a induced metabolic impairment and improves microglial phagocytic and barrier function in response to Aß pathology.

Complement C3aR is primarily expressed in microglial cells in the brain. Our study found elevated expression of C3aR in microglia in Alzheimer's disease. To understand the underlying molecular mechanism, we sorted microglia based on their C3aR expression from 9-month-old wild-type and APP-KI mice. Through RNA-seq analysis, we identified metabolic perturbations in C3aR-positive microglia from 9-month-old APP-KI mice. Furthermore, we performed RNA-seq on sorted microglial cells from wild-type, C3aR knockout, APP-KI, and APP-KI;C3aR knockout mice. This analysis revealed a dampening of metabolic dysfunction in the absence of C3aR. Overall design: Bulk RNA-seq of sorted microglia from the brains of 9-month-old WT and APP-KI based on C3aR expression; and bulk RNA-seq of sorted microglial cells from 9-month-old WT, C3aRKO, APP-KI and APP-KI;C3aRKO mice.