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Global C3 lowering alleviates hippocampal dysfunction and cognitive impairment in aged mice
Author(s) -
Batista Andre Felipe,
Schroeder Maren K,
Khan Khyrul,
Li Shaomin A,
Presumey Jessy,
Yalcin Esra,
Carroll Michael,
Lemere Cynthia A
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.058736
Subject(s) - hippocampal formation , long term potentiation , hippocampus , cohort , memory impairment , medicine , neuroscience , synapse , dementia , cognitive decline , prepulse inhibition , psychology , endocrinology , cognition , disease , psychiatry , schizophrenia (object oriented programming) , receptor
Background Complement component C3, an innate immune molecule, is important for removing pathogens and eliminating synapses during brain development, aging, and Alzheimer’s disease (AD). Previously, our group demonstrated that C3 deficiency protected against synapse loss during normal aging in wild‐type and APPswe/PS1dE9 mice. Induction of C3 deficiency after normal brain development will help inform whether its inhibition in aging or early stages of AD may serve as a future therapeutic strategy. Method We crossed C3fl/fl mice with an inducible, global Cre line (Rosa26‐Cre‐ERT2+/‐) for 2 generations to generate novel inducible C3 conditional knockout C3fl/fl; Rosa26‐Cre‐ERT2+/‐ mice (C3iKO). In one cohort, four‐to‐five‐month‐old mice were injected with tamoxifen (TAM) or corn oil (CO) daily for 5 days. Behavioral tasks were performed when these mice reached 16‐17 months of age. In another study, three‐to‐four‐month‐old female mice were injected with either CO/TAM and electrophysiological recording of long‐term potentiation (LTP) was conducted in hippocampal slices of TAM‐treated and CO‐treated mice at 7‐8 months of age following incubation of the slices with neurotoxic Aβ S26 dimers. Result C3iKO mice had a significant 85‐95% reduction in serum C3 levels compared to controls, which was consistent at all timepoints analyzed (from Day 7 to Day 365). In this cohort, 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 the second study, we found that C3 lowering in adult mice protected hippocampal synapses from Aβ S26 dimer‐mediated LTP impairment. Conclusion Global C3 depletion in C3iKO young adult mice protected against hippocampal dysfunction as they aged, suggesting that C3 lowering may be an effective therapeutic strategy for aging and possibly, AD. Future studies are underway to investigate the C3‐mediated mechanisms of synaptic dysfunction in the hippocampus.