Title:Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease
Volume: 23
Issue: 33
Author(s): Chenju Yi*, Annette Koulakoff and Christian Giaume
Affiliation:
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, 75005 Paris,France
Keywords:
Connexin, astrocyte, hemichannel, gap junction, Alzheimer's disease, amyloid plaques.
Abstract: Background: In Alzheimer's disease (AD), modification of astrocytic properties is a well-known and
documented fact, but their involvement in pathophysiology has only been examined in recent years. One distinct
hallmark of AD is reactive gliosis which are represented in microglial and astrocytic phenotype changes. This
reactive gliosis has been associated with changes in the expression and function of connexins. Connexins are
proteins that can form gap junction channels and hemichannels, and in a disease context, have shown increased
expression in astrocytes that contact amyloid plaques in vivo. Amyloid plaques are aggregates of the amyloid-beta
protein, which present in the AD brain in patients and in animal models.
Methods: Murine AD models demonstrate changes in connexin channel activity which mirror in cell culture
systems treated with amyloid-beta peptide. This has been closely studied in the familial AD mouse model APPSwe/
PS1dE9 where the implications of connexin channel functions have been examined.
Results: These studies demonstrate that while gap junctional communication was unaffected, hemichannel activation
could be detected in the astrocytes of hippocampal slices containing amyloid-beta plaques. Most critically,
the activation of hemichannels is associated with the release of gliotransmitters (such as ATP and glutamate)
which results in the maintenance of a high intracellular free Ca2+ concentration within astrocytes, which initiates
the start of a vicious cycle. Strategies that target astroglial connexin hemichannels include the knocking out of the
connexin 43 gene in astrocytes of the APPSwe/PS1dE9 mice, as well as using various pharmacological tools. This
results in the decrease of gliotransmitter release and the alleviation of neuronal damage. This includes the reduction
of oxidative stress and neuritic dystrophies in neurons that are typically associated with plaque formation in
the hippocampus.
Concusion: In this review, we summarize recent findings on astroglial connexin channels in the neurodegenerative
process of Alzheimer's disease, and discuss how this can be a strategy in AD treatment to block the activity
of hemichannels in astrocytes.
