Abstract Body

Objective: Complement C3 is an innate immune molecule that plays an important role in synapse elimination. Previously, we reported that germline deletion of complement C3 (C3KO) protected against hippocampal decline in aged C57BL/6 and APP/PS1dE9 mice. Here, we generated global and cell-specific C3 inducible conditional knockout mice.

Methods: We generated and crossed C3 floxed (C3fl/fl) mice to Rosa26-Cre-ERT2+/- mice to create a novel global C3 inducible conditional knockout (C3iKO) mouse model. Adult mice were treated with 5 daily i.p. injections of 75 mg/kg tamoxifen (TAM) or corn oil (control). C3 protein levels were quantified in serum (ELISA) and brain (Western blot) at various timepoints. Complement C3 mRNA expression was quantified by qPCR in the liver and brain post-treatment. Currently, we are crossing the C3fl/fl mice with Cx3cr1-Cre-ERT2 (YFP) mice to lower C3 in microglia (C3-mg-iKO) and Aldh1l1-Cre-ERT2 (BAC) mice to lower C3 in astrocytes (C3-as-iKO).

Results: Tamoxifen treatment of C3iKO mice resulted in reduced C3 levels in serum (~85-90%) and brain (~60%) at day 150. C3 mRNA was significantly reduced in liver and brain of C3iKO+TAM mice at 60 and 150 days. The cell-specific models are underway and thus far, show recombination in brain.

Conclusions: Our novel C3iKO mouse model shows long-term C3 lowering. We will cross these mice to amyloid and tau mouse models to determine if C3 lowering is protective during early-stage AD pathogenesis. Our novel cell-specific models will allow us to further delineate C3 signaling in brain.

Funding: NIH R21 AG044713 (CAL, MC); NIH RF1 AG060057 (CAL)