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Updated: Oct 16, 2025
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
Julien Bourel1, Vincent Planche2, Nadège Dubourdieu1
1Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France.
Abstract:
Memory impairment is one of the disabling manifestations of multiple sclerosis (MS) possibly present from the early stages of the disease and for which there is no specific treatment. Hippocampal synaptic dysfunction and dendritic loss, associated with microglial activation, can underlie memory deficits, yet the molecular mechanisms driving such hippocampal neurodegeneration need to be elucidated. In early-stage experimental autoimmune encephalomyelitis (EAE) female mice, we assessed the expression level of molecules involved in microglia-neuron interactions within the dentate gyrus and found overexpression of genes of the complement pathway. Compared to sham immunized mice, the central element of the complement cascade, C3, showed the strongest and 10-fold upregulation, while there was no increase of downstream factors such as the terminal component C5. The combination of in situ hybridization with immunofluorescence showed that C3 transcripts were essentially produced by activated microglia. Pharmacological inhibition of C3 activity, by daily administration of rosmarinic acid, was sufficient to prevent early dendritic loss, microglia-mediated phagocytosis of synapses in the dentate gyrus, and memory impairment in EAE mice, while morphological markers of microglial activation were still observed. In line, when EAE was induced in C3 deficient mice (C3KO), dendrites and spines of the dentate gyrus as well as memory abilities were preserved. Altogether, these data highlight the central role of microglial C3 in early hippocampal neurodegeneration and memory impairment in EAE and, therefore, pave the way toward new neuroprotective strategies in MS to prevent cognitive deficit using complement inhibitors.
Insights
Microglial C3 drives early memory loss in multiple sclerosis (MS) models by damaging hippocampal synapses. Inhibiting C3 or using C3-deficient mice preserves memory and neuronal structure, suggesting C3 inhibitors as a potential MS treatment.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Memory impairment is a significant disabling symptom in multiple sclerosis (MS), often appearing early in the disease.
- Hippocampal synaptic dysfunction and dendritic loss, linked to microglial activation, are implicated in MS-related memory deficits.
- The precise molecular mechanisms driving neurodegeneration in the hippocampus during MS remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms of early hippocampal neurodegeneration and memory impairment in a mouse model of MS.
- To identify key molecules involved in microglia-neuron interactions within the hippocampus during early-stage disease.
- To evaluate the therapeutic potential of targeting microglial complement C3 for preventing cognitive decline in MS.
Main Methods:
- Analysis of gene expression in the dentate gyrus of mice with experimental autoimmune encephalomyelitis (EAE), a model for MS.
- Utilizing in situ hybridization and immunofluorescence to localize C3 transcript and protein expression.
- Pharmacological inhibition of C3 activity using rosmarinic acid and assessment in C3-deficient (C3KO) EAE mice.
Main Results:
- Overexpression of complement pathway genes, particularly C3, was observed in the early stages of EAE.
- C3 transcripts were primarily produced by activated microglia in the dentate gyrus.
- Pharmacological inhibition of C3 or genetic deficiency of C3 prevented dendritic loss, synapse elimination, and memory impairment in EAE mice.
- These protective effects were observed despite continued microglial activation.
Conclusions:
- Microglial complement C3 plays a critical role in early hippocampal neurodegeneration and memory deficits in MS models.
- Targeting microglial C3 presents a promising therapeutic strategy for preventing cognitive dysfunction in multiple sclerosis.
- Complement inhibitors offer a potential avenue for neuroprotection against MS-related cognitive decline.
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