Menu
Synapse loss is a critical feature of Alzheimer’s disease (AD). C3 is the molecule at which multiple complement signaling pathways converge (Garred et al., 2021) and has emerged as a key factor in synapse elimination during the development of the central nervous system (Stevens et al., 2007), aging and AD (Wu et al., 2019). The Lemere lab has previously reported that C3-deficiency is protective against age- and AD-dependent synaptic degeneration and cognitive decline (Shi et al., 2015, 2017). Here, we aimed to define the underlying cell-specific mechanisms of either microglia or astrocytes that lead to C3-dependent synaptic toxicity and neurodegeneration. To this end, we generated cell-specific C3 tamoxifen (TAM)-inducible conditional knock-out (KO) mice to allow for specific KO of C3 in microglia (C3mg-iKO) and astrocytes (C3as-iKO). Young adult female and male mice were injected intraperitoneally with either corn oil (CO) as control or TAM once every 24 hours for 5 consecutive days (75mg/kg body weight). Following TAM/CO treatment mice underwent a battery of behavioral, biochemical, and histological analyses. Aged TAM-treated C3mg-iKO mice performed significantly better in behavioral tests of spatial memory, showed a modest lowering of C3 and C1q protein levels in the hippocampus and a 30% lowering of C3 mRNA expression levels compared to controls. Aged TAM-treated C3as-iKO mice demonstrated a modest increase in post-synaptic density in the hippocampus and a 50% lowering of C3 and clusterin mRNA expression levels compared to controls. Furthermore, C3 lowering in astrocytes significantly protected hippocampal synapses from Aβ-dimer-mediated LTP impairment in TAM-treated C3as-iKO mice. Neither model resulted in significant changes in serum C3 protein levels. These results indicate the essential implication of glial cells in C3-mediated neurodegeneration and highlight the importance of further understanding the interactions between C3 and the glial cells that lead to synapse loss during aging and AD. Further investigation of these interactions may play a key role in developing therapeutic targets for tackling AD and other neurodegenerative disorders.
Funded by NIH/NIA RF1 AG060057 (CAL)
