September 29, 2021

Global C3 lowering alleviates hippocampal dysfunction and cognitive impairment in aged mice

Andre Batista, PhD

Additional Authors: Maren K. Schroeder, Khyrul Khan, Shaomin Li, Jessy Presumey, Esra Yalcin, Michael Carroll, and Cynthia A. Lemere

The complement cascade modulates the innate immune system, which leads to the elimination of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. Complement C3 is part of the innate immune system and participates in synapse elimination during normal brain development to refine neuronal networks. Further, this molecule may be detrimental in several neurodegenerative diseases, including Alzheimer’s disease (AD). C3 levels in the brain are elevated during aging and AD. Our group previously showed that lifelong C3-deficiency protected against hippocampal synapse loss in aged WT and APP/PS1dE9 mice, correlating with improved performance on cognitive tests. Recently, we developed an inducible conditional C3 knockout mouse model (C3iKO) by crossing C3 floxed (C3fl/fl) mice with Rosa26-Cre-ERT2+/- mice on a C57BL/6J background. Our goal was to investigate whether C3 lowering in adulthood, after normal brain development, would still protect hippocampal function in these mice. First, 4–5-month-old male and female C3iKO mice were i.p. injected with tamoxifen (TAM) or corn oil (CO; control) daily for 5 days. Tamoxifen treatment of C3iKO mice led to a sustained ~95% lowering of serum C3 levels. Behavioral testing for hippocampal-dependent spatial memory, object memory, and object location was performed when TAM-treated and CO-treated mice reached 16-17 months of age. C3iKO+TAM mice performed significantly better than C3iKO+CO-treated mice in these behavioral tasks, indicating that C3 lowering after brain development protected mice from age-related cognitive decline. In another study, mice were treated with TAM or CO at 3-4 months of age and electrophysiological recording of long-term potentiation (LTP) was conducted 3 months later in hippocampal slices incubated with neurotoxic Aβ S26 dimers. Remarkably, C3 lowering protected hippocampal synapses from Aβ S26 dimer-mediated LTP impairment. In conclusion, 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 AD.

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