Microglial deletion of C1q rescues AD cognitive decline and synaptic loss

Abstract Background The complement (C’) system contributes to enhanced inflammation and cognitive decline in Alzheimer’s disease (AD). Previous studies have demonstrated constitutive deletion of the classical initiator protein, C1q, reduces pathology and synaptic loss in AD mouse model. As it is now known that microglia are the primary producers of C1q in the brain, the main objective of this study was to determine if microglial specific deletion of C1q would rescue cognitive impairment and synaptic loss in AD. Method C1qa FLlFL :CX3CR1Cre (designated C1q ΔMG )mice, which experience tamoxifen‐independent deletion of microglial C1q by 2 months of age, were crossed to Arctic: C1qa Fl/Fl: mice to generate WT and Artic mice with and without the CX3CR1Cre transgene. At 10 months of age, mice underwent behavioral testing of hippocampal dependent spatial memory, including object location memory (OLM) and spatial reference Y‐maze. Tissue was collected at the end of testing and immunostained for pre (VGlut1) and post (PSD95) synaptic makers and Z‐stacks using superresolution microscopy in the CA1 of the hippocampus were obtained. The density of pre‐ and post‐synaptic puncta and their colocalization was assessed using IMARIS. Result While both male and female Arctic mice displayed a significant impairment in long‐term memory, as assessed by OLM, microglial deletion of C1q rescued cognitive deficits in male but not female Arctic mice. Male Arctic C1q ΔMG mice also performed better on Y‐maze testing than Arctic controls. Similar sex‐dependent results were observed in synaptic density. Female Arctic C1q ΔMG mice displayed reduced levels of PSD95 and Vglut1 puncta compared to female Arctic mice, as well as a trending reduction in colocalization. In contrast, male Arctic C1q ΔMG mice displayed increased levels of PSD95, trending reductions in VGlut1 compared to male Arctic controls, and trending increases in synaptic colocalization, suggesting an increase in functional synapses in the male mouse. Conclusion Deletion of C1q in microglia prior to amyloid plaque deposition protects against cognitive decline and synaptic loss in a greater extent in males than females.