title: Astroglial connexin43 contributes to neuronal suffering in a mouse model of Alzheimer's disease.
abstract: In Alzheimer's disease (AD), astrocyte properties are modified but their involvement in this pathology is only beginning to be appreciated. The expression of connexins, proteins forming gap junction channels and hemichannels, is increased in astrocytes contacting amyloid plaques in brains of AD patients and APP/PS1 mice. The consequences on their channel functions was investigated in a murine model of familial AD, the APPswe/PS1dE9 mice. Whereas gap junctional communication was not affected, we revealed that hemichannels were activated in astrocytes of acute hippocampal slices containing Aβ plaques. Such hemichannel activity was detected in all astrocytes, whatever their distance from amyloid plaques, but with an enhanced activity in the reactive astrocytes contacting amyloid plaques. Connexin43 was the main hemichannel contributor, however, a minor pannexin1 component was also identified in the subpopulation of reactive astrocytes in direct contact with plaques. Distinct regulatory pathways are involved in connexin and pannexin hemichannel activation. Inflammation triggered pannexin hemichannel activity, whereas connexin43 hemichannels were activated by the increase in resting calcium level of astrocytes. Importantly, hemichannel activation led to the release of ATP and glutamate that contributed to maintain a high calcium level in astrocytes placing them in the center of a vicious circle. The astroglial targeted connexin43 gene knocking-out in APPswe/PS1dE9 mice allowed to diminish gliotransmitter release and to alleviate neuronal damages, reducing oxidative stress and neuritic dystrophies in hippocampal neurons associated to plaques. Altogether, these data highlight the importance of astroglial hemichannels in AD and suggest that blocking astroglial hemichannel activity in astrocytes could represent an alternative therapeutic strategy in AD.
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), Collège de France, 75005 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7241, 75005 Paris, France.|Institut National de la Santé et de la Recherche Médicale U1050, 75005 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Yi
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), Collège de France, 75005 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7241, 75005 Paris, France.|Institut National de la Santé et de la Recherche Médicale U1050, 75005 Paris, France.
authors.forename: X
authors.initials: X
authors.lastname: Mei
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), Collège de France, 75005 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7241, 75005 Paris, France.|Institut National de la Santé et de la Recherche Médicale U1050, 75005 Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Ezan
authors.affiliation: Achucarro Basque Center for Neuroscience, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.|Departamento de Neurociencias, Universidad del Pais Vasco, Leioa, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Mato
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1215, Neurocentre Magendie, 33077 Bordeaux, France.|Université de Bordeaux, 33077 Bordeaux, France.
authors.forename: I
authors.initials: I
authors.lastname: Matias
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), Collège de France, 75005 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7241, 75005 Paris, France.|Institut National de la Santé et de la Recherche Médicale U1050, 75005 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Giaume
authors.affiliation: Center for Interdisciplinary Research in Biology (CIRB), Collège de France, 75005 Paris, France.|Centre National de la Recherche Scientifique Unité Mixte de Recherche 7241, 75005 Paris, France.|Institut National de la Santé et de la Recherche Médicale U1050, 75005 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Koulakoff
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication; D002463:Cell Membrane Permeability; D018031:Connexin 43 / Q000378:metabolism*; D004195:Disease Models, Animal; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D053764:Presenilin-1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018031:Connexin 43; D053764:Presenilin-1; D002118:Calcium