Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
Neurobiology of Disease. 2021-12-01; 160: 105533
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Bourel J(1), Planche V(2), Dubourdieu N(1), Oliveira A(1), Séré A(3), Ducourneau EG(1), Tible M(1), Maitre M(1), Lesté-Lasserre T(1), Nadjar A(4), Desmedt A(1), Ciofi P(1), Oliet SH(1), Panatier A(1), Tourdias T(5).
(1)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France.
(2)Univ. Bordeaux, CNRS, UMR 5293, Institut des Maladies Neurodégénératives, F-33000 Bordeaux, France.
(3)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France.
(4)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France; Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France.
(5)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France; CHU de Bordeaux, Neuroimagerie diagnostique et thérapeutique, F-33000 Bordeaux, France. Electronic address: .
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 isno 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 beelucidated. 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.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.