Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis.

Brain, Behavior, and Immunity
Jennetta W. HammondHarris A Gelbard

Abstract

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 MOG35-55 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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Citations

Nov 27, 2020·Journal of Neuroinflammation·Nicole D Schartz, Andrea J Tenner
Jan 27, 2021·Nature Neuroscience·Mehrnoosh JafariMartin Kerschensteiner
Oct 30, 2020·Pharmaceuticals·Maria GavriilakiEleni Gavriilaki
Mar 3, 2021·CNS Neuroscience & Therapeutics·Ke WangYanqin Gao
Feb 19, 2021·Proceedings of the National Academy of Sciences of the United States of America·Yee Ming KhawMakoto Inoue
Mar 27, 2021·Journal of Translational Medicine·Zijian LiJuan Feng
May 1, 2021·International Journal of Molecular Sciences·Karolina ZiabskaTeresa Zalewska
Jun 15, 2021·Multiple Sclerosis : Clinical and Laboratory Research·Marco VercellinoPaola Cavalla
Aug 16, 2021·Brain, Behavior, and Immunity·Francesca Romana RizzoAntonietta Gentile
Sep 7, 2021·Acta Neuropathologica·Marjan GharagozlooPeter A Calabresi

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