Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease
Department of Neurobiology, Brudnik Neuropsychiatric Research Institute; Horae Gene Therapy Center; Li Weibo Institute for Rare Diseases Research; Department of Microbiologic and Physiological Systems; Schafer Lab
Immunity | Nervous System | Nervous System Diseases | Neuroscience and Neurobiology
Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on myelin and axon loss in MS, less is known about mechanisms underlying synaptic changes. Using postmortem human MS tissue, a preclinical nonhuman primate model of MS, and two rodent models of demyelinating disease, we investigated synapse changes in the visual system. Similar to other neurodegenerative diseases, microglial synaptic engulfment and profound synapse loss were observed. In mice, synapse loss occurred independently of local demyelination and neuronal degeneration but coincided with gliosis and increased complement component C3, but not C1q, at synapses. Viral overexpression of the complement inhibitor Crry at C3-bound synapses decreased microglial engulfment of synapses and protected visual function. These results indicate that microglia eliminate synapses through the alternative complement cascade in demyelinating disease and identify a strategy to prevent synapse loss that may be broadly applicable to other neurodegenerative diseases. VIDEO ABSTRACT.
complement, demyelination, engulfment, gene therapy, microglia, multiple sclerosis, neural-immune, neurodegeneration, neuroinflammation, synapse
DOI of Published Version
Immunity. 2020 Jan 14;52(1):167-182.e7. doi: 10.1016/j.immuni.2019.12.004. Epub 2019 Dec 26. Link to article on publisher's site
Werneburg S, Jung J, Kunjamma RB, Ha S, Luciano NJ, Willis CM, Gao G, Biscola NP, Havton LA, Crocker SJ, Popko B, Reich DS, Schafer DP. (2020). Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease. Neurobiology Publications. https://doi.org/10.1016/j.immuni.2019.12.004. Retrieved from https://escholarship.umassmed.edu/neurobiology_pp/253