Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease

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dc.contributor.authorWerneburg, Sebastian
dc.contributor.authorJung, Jonathan
dc.contributor.authorKunjamma, Rejani B.
dc.contributor.authorHa, Seung-Kwon
dc.contributor.authorLuciano, Nicholas J.
dc.contributor.authorWillis, Cory M.
dc.contributor.authorGao, Guangping
dc.contributor.authorBiscola, Natalia P.
dc.contributor.authorHavton, Leif A.
dc.contributor.authorCrocker, Stephen J.
dc.contributor.authorPopko, Brian
dc.contributor.authorReich, Daniel S.
dc.contributor.authorSchafer, Dorothy P
dc.contributor.departmentSchafer Lab
dc.contributor.departmentMicrobiology and Physiological Systems
dc.contributor.departmentLi Weibo Institute for Rare Diseases Research
dc.contributor.departmentHorae Gene Therapy Center
dc.contributor.departmentNeurobiology
dc.contributor.departmentBrudnick Neuropsychiatric Research Institute
dc.date2022-08-11T08:09:29.000
dc.date.accessioned2022-08-23T16:32:54Z
dc.date.available2022-08-23T16:32:54Z
dc.date.issued2020-01-14
dc.date.submitted2020-01-22
dc.description.abstractMultiple 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.
dc.identifier.citation<p>Immunity. 2020 Jan 14;52(1):167-182.e7. doi: 10.1016/j.immuni.2019.12.004. Epub 2019 Dec 26. <a href="https://doi.org/10.1016/j.immuni.2019.12.004">Link to article on publisher's site</a></p>
dc.identifier.contextkey16308773
dc.identifier.doi10.1016/j.immuni.2019.12.004
dc.identifier.issn1074-7613 (Linking)
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/neurobiology_pp/253
dc.identifier.pmid31883839
dc.identifier.submissionpathneurobiology_pp/253
dc.identifier.urihttps://hdl.handle.net/20.500.14038/37981
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31883839&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1016/j.immuni.2019.12.004
dc.source.issue1
dc.source.journaltitleImmunity
dc.source.pages167-182.e7
dc.source.volume52
dc.subjectcomplement
dc.subjectdemyelination
dc.subjectengulfment
dc.subjectgene therapy
dc.subjectmicroglia
dc.subjectmultiple sclerosis
dc.subjectneural-immune
dc.subjectneurodegeneration
dc.subjectneuroinflammation
dc.subjectsynapse
dc.subjectImmunity
dc.subjectNervous System
dc.subjectNervous System Diseases
dc.subjectNeuroscience and Neurobiology
dc.titleTargeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease
dc.typeJournal Article
dspace.entity.typePublication
html.description.abstract<p>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.</p>
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