Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis

• Published in: Neurobiology of disease Vol. 160; p. 105533
• Main Authors: Bourel, Julien, Planche, Vincent, Dubourdieu, Nadège, Oliveira, Aymeric, Séré, Alexandra, Ducourneau, Eva-Gunnel, Tible, Marion, Maitre, Marlène, Lesté-Lasserre, Thierry, Nadjar, Agnes, Desmedt, Aline, Ciofi, Philippe, Oliet, Stéphane H., Panatier, Aude, Tourdias, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2021; Elsevier
• Subjects: Animals; Cinnamates - pharmacology; Complement; Complement C3 - antagonists & inhibitors; Complement C3 - genetics; Complement C3 - metabolism; Complement C3-C5 Convertases - pharmacology; Dendrites - drug effects; Dendrites - metabolism; Depsides - pharmacology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Life Sciences; Memory deficit; Memory Disorders - metabolism; Memory Disorders - pathology; Mice; Mice, Knockout; Microglia; Microglia - drug effects; Microglia - metabolism; Molybdoferredoxin; Multiple sclerosis; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurodegeneration; Neurons and Cognition; Phagocytosis - drug effects; Rosmarinic Acid; Synapses - drug effects; Synapses - metabolism; Multiple sclerosis; Complement; hippocampus; Neurodegeneration; Memory deficit; Microglia
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2021.105533

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. [Display omitted] •Complement cascade, especially C3, is upregulated in EAE dentate gyrus.•Microglia is the main source of C3 production in EAE dentate gyrus.•C3 inhibition reduces microglial dependent synaptic loss in EAE dentate gyrus.•C3 inhibition preserves memory performances in EAE mice.