A novel inducible Complement C3 conditional knockout mouse model: generation and characterization

Andre Batista, PhD
Department of Neurology
Poster Overview

The classical complement pathway is a complex process involved in the elimination of dead cells, debris, and pathogens, and as well as brain wiring during development. Complement protein C3 is a molecule central in the complement pathway. It participates in removing pathogens and eliminating synapses. This molecule is elevated with aging and Alzheimer's Disease (AD). Our group showed previously that C3-deficiency protected aged male wild-type and transgenic mice against hippocampal neuronal dysfunction and cognitive decline. However, it remains unknown whether suppressing complement C3 signaling during early stages of AD pathogenesis. To address this question, we generate a new mouse model where after a treatment with tamoxifen,
we can decrease C3 levels globally throughout the whole body of mouse. We showed that mice had a significant 70% reduction in serum C3 levels compared to controls. We also showed that C3 expression in the liver as well as in the brain was reduced. In conclusion, we present a novel mouse model in which tamoxifen treatment resulted in sustained lowering of C3 in the serum, liver, and brain. Next step will be to evaluate whether global C3 lowering in early stages AD pathogenesis is protective.

Scientific Abstract

Complement protein C3 is an innate immune molecule central in the complement pathway. It participates in removing pathogens and eliminating synapses, and is elevated with aging and Alzheimer's Disease. Previously, we showed that lifelong, germline C3-deficiency protected aged male wild-type and APPswe/PS1dE9 mice against hippocampal neuronal dysfunction and cognitive decline, despite increasing the A� plaque load. However, it remains unknown whether suppressing complement C3 signaling during early stages of AD pathogenesis. To address this question, we generated the first-ever C3 floxed (C3fl/fl) mouse line, and then crossed the C3fl/fl mice with an inducible, global Cre line (Rosa26-Cre-ERT2+/-) to generate a novel inducible C3 conditional knockout C3fl/fl; Rosa26-Cre-ERT2+/- mice (C3iKO). C3iKO mice had a significant 70% reduction in serum C3 levels compared to controls. We also showed that C3 expression in the liver as well as in the brain was reduced. In conclusion, we present a novel mouse model in which tamoxifen treatment resulted in sustained lowering of C3 in the serum, liver, and brain. We will next cross this model with AD-like mouse models to evaluate whether global C3 lowering in early stages AD pathogenesis is protective and if so, our data would support targeting complement as a therapy for AD.

Clinical Implications
This study may guide complement-lowering therapies for AD and other neurodegenerative diseases and will provide novel research models to many fields.
Research Areas
Authors
Andre F. Batista, Maren Schroeder, Khyrul Khan, Esra Yalcin, Michael Carroll, Cynthia A. Lemere
Principal Investigator
Cynthia A. Lemere

Explore Other Posters

Leave a Reply

Your email address will not be published. Required fields are marked *