Astroglial connexin43 contributes to neuronal suffering in a mouse model of Alzheimer’s disease

C Yi, X Mei, P Ezan, S Mato, I Matias, C Giaume, A Koulakoff
Cell Death Differ. 2016-07-08; 23(10): 1691-1701
DOI: 10.1038/cdd.2016.63

Read on PubMed

1. Cell Death Differ. 2016 Oct;23(10):1691-701. doi: 10.1038/cdd.2016.63. Epub
2016 Jul 8.

Astroglial connexin43 contributes to neuronal suffering in a mouse model of
Alzheimer’s disease.

Yi C(1)(2)(3), Mei X(1)(2)(3), Ezan P(1)(2)(3), Mato S(4)(5), Matias I(6)(7),
Giaume C(1)(2)(3), Koulakoff A(1)(2)(3).

Author information:
(1)Center for Interdisciplinary Research in Biology (CIRB), Collège de France,
75005 Paris, France.
(2)Centre National de la Recherche Scientifique Unité Mixte de Recherche 7241,
75005 Paris, France.
(3)Institut National de la Santé et de la Recherche Médicale U1050, 75005 Paris,
(4)Achucarro Basque Center for Neuroscience, Centro de Investigación Biomédica
en Red en Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.
(5)Departamento de Neurociencias, Universidad del Pais Vasco, Leioa, Spain.
(6)Institut National de la Santé et de la Recherche Médicale U1215, Neurocentre
Magendie, 33077 Bordeaux, France.
(7)Université de Bordeaux, 33077 Bordeaux, France.

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.

DOI: 10.1038/cdd.2016.63
PMCID: PMC5041199
PMID: 27391799 [Indexed for MEDLINE]

Know more about