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Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating
Sebastian Werneburg1, Jonathan Jung1, Rejani B Kunjamma2
1Department of Neurobiology, Brudnik Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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.
Insights
Microglia eliminate synapses in multiple sclerosis (MS) via the complement cascade. Inhibiting complement component C3 protected synapses and visual function in preclinical models.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Multiple sclerosis (MS) is a central nervous system demyelinating autoimmune disease.
- Synaptic changes in MS are less understood than myelin and axon loss.
- Investigating synaptic mechanisms is crucial for understanding MS neurodegeneration.
Purpose of the Study:
- To investigate synapse changes in the visual system in multiple sclerosis.
- To elucidate the mechanisms underlying microglial-mediated synapse loss.
- To identify potential therapeutic targets for preventing synapse loss in MS.
Main Methods:
- Analysis of postmortem human MS tissue.
- Utilized nonhuman primate and rodent models of demyelinating disease.
- Examined microglial synaptic engulfment, complement deposition, and viral gene delivery for complement inhibition.
Main Results:
- Observed microglial synaptic engulfment and significant synapse loss in MS models.
- Synapse loss occurred independently of demyelination but correlated with complement C3 deposition.
- Inhibiting complement C3 reduced microglial synapse engulfment and preserved visual function.
Conclusions:
- Microglia eliminate synapses through the alternative complement cascade in demyelinating diseases like MS.
- Targeting complement component C3 offers a potential strategy to prevent synapse loss.
- This approach may be broadly applicable to other neurodegenerative conditions.
