UC Irvine

C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, is primarily expressed on cells of the myeloid lineage, and to a lesser extent on endothelial cells and neurons in brain. Previous work demonstrated that a C5aR1 antagonist, PMX205, decreased amyloid pathology and suppressed cognitive deficits in Alzheimer disease (AD) mouse models. However, the cellular mechanisms of this protection have not been definitively demonstrated. Here, we show that C5a can induce neuronal cell death. Both pharmacologic and genetic data indicate that C5aR1 is required for the C5a-induced decrease of neuron MAP-2. Additionally, in the context of AD, we show that increased neuronal damage is caused by the addition of C5a to neurons treated with fAβ, and can be blocked by the C5aR1 antagonist, PMX53.To understand the role of microglial C5aR1 in an AD mouse model, CX3CR1GFP and CCR2RFP reporter mice were bred to C5aR1 sufficient and knockout wild type and Arctic mice. Microglia (GFP-positive, RFP-negative) and infiltrating monocytes (GFP and RFP-positive) were sorted for transcriptome analysis at 2, 5, 7 and 10 months of age. Immunohistochemical analysis showed no CCR2+ monocytes/macrophages near the plaques in the Arctic brain with or without C5aR1. RNA-seq analysis on microglia from these mice identified inflammation related genes as differentially expressed, with increased expression in the Arctic mice relative to wildtype and decreased expression in the Arctic/C5aR1KO relative to Arctic. In addition, phagosomal-lysosomal genes were increased in the Arctic mice and further increased in the Arctic/C5aR1KO mice. These data are consistent with a microglial polarization state in the absence of C5aR1 signaling with restricted induction of inflammatory genes and enhancement of degradation/clearance pathways and support the potential of this receptor as a novel therapeutic target for AD in humans.