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

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 defi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Julien Bourel, Vincent Planche, Nadège Dubourdieu, Aymeric Oliveira, Alexandra Séré, Eva-Gunnel Ducourneau, Marion Tible, Marlène Maitre, Thierry Lesté-Lasserre, Agnes Nadjar, Aline Desmedt, Philippe Ciofi, Stéphane H. Oliet, Aude Panatier, Thomas Tourdias
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Multiple sclerosis Memory deficit hippocampus Neurodegeneration Complement Microglia Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/2795f1f4556d468198d33235f37e06f4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2795f1f4556d468198d33235f37e06f4
record_format	dspace
spelling	oai:doaj.org-article:2795f1f4556d468198d33235f37e06f42021-11-12T04:26:23ZComplement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis1095-953X10.1016/j.nbd.2021.105533https://doaj.org/article/2795f1f4556d468198d33235f37e06f42021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121002825https://doaj.org/toc/1095-953XMemory 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.Julien BourelVincent PlancheNadège DubourdieuAymeric OliveiraAlexandra SéréEva-Gunnel DucourneauMarion TibleMarlène MaitreThierry Lesté-LasserreAgnes NadjarAline DesmedtPhilippe CiofiStéphane H. OlietAude PanatierThomas TourdiasElsevierarticleMultiple sclerosisMemory deficithippocampusNeurodegenerationComplementMicrogliaNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 160, Iss , Pp 105533- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Multiple sclerosis Memory deficit hippocampus Neurodegeneration Complement Microglia Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Multiple sclerosis Memory deficit hippocampus Neurodegeneration Complement Microglia Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Julien Bourel Vincent Planche Nadège Dubourdieu Aymeric Oliveira Alexandra Séré Eva-Gunnel Ducourneau Marion Tible Marlène Maitre Thierry Lesté-Lasserre Agnes Nadjar Aline Desmedt Philippe Ciofi Stéphane H. Oliet Aude Panatier Thomas Tourdias Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
description	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.
format	article
author	Julien Bourel Vincent Planche Nadège Dubourdieu Aymeric Oliveira Alexandra Séré Eva-Gunnel Ducourneau Marion Tible Marlène Maitre Thierry Lesté-Lasserre Agnes Nadjar Aline Desmedt Philippe Ciofi Stéphane H. Oliet Aude Panatier Thomas Tourdias
author_facet	Julien Bourel Vincent Planche Nadège Dubourdieu Aymeric Oliveira Alexandra Séré Eva-Gunnel Ducourneau Marion Tible Marlène Maitre Thierry Lesté-Lasserre Agnes Nadjar Aline Desmedt Philippe Ciofi Stéphane H. Oliet Aude Panatier Thomas Tourdias
author_sort	Julien Bourel
title	Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
title_short	Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
title_full	Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
title_fullStr	Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
title_full_unstemmed	Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
title_sort	complement c3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/2795f1f4556d468198d33235f37e06f4
work_keys_str_mv	AT julienbourel complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT vincentplanche complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT nadegedubourdieu complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT aymericoliveira complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT alexandrasere complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT evagunnelducourneau complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT mariontible complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT marlenemaitre complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT thierrylestelasserre complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT agnesnadjar complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT alinedesmedt complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT philippeciofi complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT stephaneholiet complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT audepanatier complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis AT thomastourdias complementc3mediatesearlyhippocampalneurodegenerationandmemoryimpairmentinexperimentalmultiplesclerosis
_version_	1718431279154724864

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

Ejemplares similares