Young adult microglial deletion of C1q reduces engulfment of synapses and prevents cognitive impairment in an aggressive Alzheimer's disease mouse model

Abstract

C1q is a multifunctional protein, including its role as the initiating protein of the classical complement cascade. While classical pathway activation is involved in synaptic pruning during development of the nervous system, it also contributes to enhanced inflammation and cognitive decline in Alzheimers disease (AD). Constitutive genetic C1q deficiency has been shown to reduce glial activation and attenuate neuronal loss in AD mouse models, but the specific contributions of microglial C1q to AD pathology while avoiding deficits during post-natal development remain to be determined. To dissect specific role(s) of microglial C1q in AD progression, we crossed the Cx3cr1CreERT2 mouse model that deletes C1q from microglia in young adulthood (8 weeks of age) to the aggressive Arctic48 (Arc) amyloidosis mouse model. At 10 months, young adult microglial C1q deletion (Arc C1q{Delta}MG) rescued cognitive deficits in spatial memory, despite unchanged amyloid plaque burden. Furthermore, Arc C1q{Delta}MG mice exhibited reduced hippocampal C3 protein levels without altering C3 mRNA. No changes were observed in C5aR1, astrocyte GFAP, or microglial Iba1 protein expression. However, Arc C1q{Delta}MG mice demonstrated region specific reductions in microglial synaptic engulfment, alongside decreased phagolysosome-associated amyloid in both microglia and astrocytes, and reduced compaction of amyloid within the hippocampus. These findings support a role for C1q in astrocytic C3 induction and the engulfment of both synapses and amyloid. Importantly, young adult microglial C1q inhibition confers cognitive benefits without exacerbating amyloid pathology, suggesting a therapeutic window in which targeting microglial C1q may mitigate neuroinflammation and synaptic loss during the later stages of AD. Main PointsO_LIYoung adult deletion of microglial C1q reduced engulfment of Vglut1+ synapses and preserved spatial cognition at 10 months of age in AD mice. C_LIO_LIFibrillar amyloid plaques nor soluble or insoluble A{beta} levels in the hippocampus were affected by young adult microglial loss of C1q despite reduced phagocytosis of amyloid by both microglia and astrocytes. C_LIO_LILoss of microglial C1q reduced C3 levels but did not affect astrocytic GFAP expression in AD mice indicating altered polarization of astrocytes. C_LI