Global complement C3 lowering in adult mice protects hippocampal synaptic function.

Abstract

Complement C3 is part of the innate immune system's host-defense against pathogens and also participates in microglial-mediated synaptic elimination during brain development to refine neuronal networks. C3 levels in brain are elevated with aging and even more so with Alzheimer's disease. Previously, we showed that lifelong C3-deficiency protected hippocampal synapses in aged WT and APP/PS1dE9 mice, resulting in a sparing of cognitive decline. More recently, we developed an inducible conditional C3 knockout mouse model (C3iKO) by crossing our C3fl/fl mice with Rosa26-Cre-ERT2+/- mice (Jackson Laboratories) on a C57BL/6J background to ask whether C3 lowering in adulthood, after brain development, would still protect hippocampal synapses. Three-to-four month-old male and female C3iKO mice were i.p. injected with tamoxifen (TAM) or corn oil (CO) daily for 5 days. In one study, behavioral testing for hippocampal-dependent spatial memory, object memory and object location was performed when C3iKO+TAM and C3iKO+CO treated mice reached 16-17 months of age (n=7-9 mice per group). In another study, electrophysiological recordings of long-term potentiation (LTP) were conducted in hippocampal slices (8-9/group) from 7-8 month-old C3iKO+TAM and C3iKO+CO mice following incubation of the slices with neurotoxic Aβ S26 dimers (5nM). Tamoxifen treatment of C3iKO mice led to a sustained ∼95% lowering of serum C3 levels in mice. Aged C3iKO+TAM mice performed better than C3iKO+CO mice in the Spatial Novelty Y Maze (trend, p = 0.07), Novel Object Recognition (p < 0.01) and Novel Object Location (p < 0.05) tests, indicating that C3 lowering after brain development protected mice from age-related cognitive decline. C3 lowering in C3iKO+TAM mice protected hippocampal synapses from Aβ S26 dimer-mediated LTP impairment. Global C3 lowering in C3iKO young adult mice protected against hippocampal dysfunction many months later, suggesting that targeting C3 may be an effective therapeutic strategy for Alzheimer's disease.