Abstract
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: The mechanisms underlying synaptic changes in multiple sclerosis (MS) remain unclear. Werneburg et al. identify microglia-mediated synapse engulfment and synapse loss in MS patients and multiple MS-relevant animal models. Synapse loss can occur early and prior to other MS-relevant pathology and is associated with synapse-localized complement C3. An AAV approach to inhibit C3 protects synapses and preserves circuit function.
Original language | English (US) |
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Pages (from-to) | 167-182.e7 |
Journal | Immunity |
Volume | 52 |
Issue number | 1 |
DOIs | |
State | Published - Jan 14 2020 |
Funding
We thank Dr. Christopher C. Hemond (UMMS) for critical reading of the manuscript. We thank Dr. Paola Perrat (UMMS) for advice on the design and production of plasmids, Shannon Becker (UMMS) and Anoushka Lotun (UMMS) for assistance with tissue preparation, and Dr. Claudio Punzo and Georgia Gunner for advice and training on optomotor testing. We further thank Prof. Dr. Matthew Rasband (Baylor College of Medicine) for sharing CASPR and βIV-spectrin specific antibodies and Prof. Oleg Butovsky for providing P2RY12 specific antibodies. This work was supported by Deutsche Forschungsgemeinschaft (DFG, Germany) grant WE 6170/1-1 (S.W.), NIMH— RO1MH113743 (D.P.S.), the Intramural Research Program of NINDS (D.S.R.), NINDS— R01NS099334 (B.P.), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.P.S., D.S.R., B.P., L.A.H.). We thank Dr. Christopher C. Hemond (UMMS) for critical reading of the manuscript. We thank Dr. Paola Perrat (UMMS) for advice on the design and production of plasmids, Shannon Becker (UMMS) and Anoushka Lotun (UMMS) for assistance with tissue preparation, and Dr. Claudio Punzo and Georgia Gunner for advice and training on optomotor testing. We further thank Prof. Dr. Matthew Rasband (Baylor College of Medicine) for sharing CASPR and ?IV-spectrin specific antibodies and Prof. Oleg Butovsky for providing P2RY12 specific antibodies. This work was supported by Deutsche Forschungsgemeinschaft (DFG, Germany) grant WE 6170/1-1 (S.W.), NIMH?RO1MH113743 (D.P.S.), the Intramural Research Program of NINDS (D.S.R.), NINDS?R01NS099334 (B.P.), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.P.S. D.S.R. B.P. L.A.H.). S.W. and D.P.S. designed the study and wrote the manuscript. S.W. performed and analyzed the experiments. J.J. assisted with mouse maintenance and conduction and analysis of experiments. S.J.C. and C.M.W. provided first murine EAE tissue and assisted in establishing the EAE mouse model. G.G. assisted with viral vector production. B.P. and R.B.K. maintained DTA mice and collected tissue for analyses. D.S.R. supervised collection and processing of human brain tissue by S.-K.H. and treatment and collection of marmoset tissue by N.J.L. N.P.B. and L.A.H. assisted with electron microscopy studies and measurements of G-ratios. All authors revised the manuscript for intellectually important content. The authors declare no conflict of interest.
Keywords
- complement
- demyelination
- engulfment
- gene therapy
- microglia
- multiple sclerosis
- neural-immune
- neurodegeneration
- neuroinflammation
- synapse
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases