Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 87, Issue -, Pages 739-750Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2020.03.004
Keywords
Complement; EAE; Multiple sclerosis; C1q; C3; Synapse; Microglia; Grey matter degeneration
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Funding
- National Multiple Sclerosis Society: NMSS [RG-1607-25423]
- National Institutes of Health [1R44NS092137, 1R21NS111255]
- Harry T. Mangurian Jr. Foundation
- University of Rochester Department of Neurology Flanagan Endowment for MS Research
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Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the CNS characterized by both grey and white matter injury. Microglial activation and a reduction in synaptic density are key features of grey matter pathology that can be modeled with MOG(35-55) experimental autoimmune encephalomyelitis (EAE). Complement deposition combined with microglial engulfment has been shown during normal development and in disease as a mechanism for pruning synapses. We tested whether there is excess complement production in the EAE hippocampus and whether complement-dependent synapse loss is a source of degeneration in EAE using C1qa and C3 knockout mice. We found that C1q and C3 protein and mRNA levels were elevated in EAE mice. Genetic loss of C3 protected mice from EAE-induced synapse loss, reduced microglial activation, decreased the severity of the EAE clinical score, and protected memory/freezing behavior after contextual fear conditioning. C1qa KO mice with EAE showed little to no change on these measurements compared to WT EAE mice. Thus, pathologic expression and activation of the early complement pathway, specifically at the level of C3, contributes to hippocampal grey matter pathology in the EAE.
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