C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease

Abstract INTRODUCTION Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement‐mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD. METHODS A combination of super‐resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD. RESULTS Genetic ablation or pharmacological inhibition of C5aR1 partially rescues excessive pre‐synaptic pruning and synaptic loss in an age and region‐dependent fashion in two mouse models of AD, which correlates with improved long‐term potentiation (LTP). DISCUSSION Reduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a‐C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD. Highlights C5aR1 ablation restores long‐term potentiation in the Arctic model of AD. C5aR1 ablation rescues region specific excessive pre‐synaptic loss. C5aR1 antagonist, PMX205, rescues VGlut1 loss in the Tg2576 model of AD. C1q tagging is not sufficient to induce VGlut1 microglial ingestion. Astrocytes contribute to excessive pre‐synaptic loss at late stages of the disease.