RT Journal Article
SR Electronic
T1 Amyloid β-Induced Death in Neurons Involves Glial and Neuronal Hemichannels
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4962
OP 4977
DO 10.1523/JNEUROSCI.6417-10.2011
VO 31
IS 13
A1 Juan A. Orellana
A1 Kenji F. Shoji
A1 Verónica Abudara
A1 Pascal Ezan
A1 Edwige Amigou
A1 Pablo J. Sáez
A1 Jean X. Jiang
A1 Christian C. Naus
A1 Juan C. Sáez
A1 Christian Giaume
YR 2011
UL http://www.jneurosci.org/content/31/13/4962.abstract
AB The mechanisms involved in Alzheimer's disease are not completely understood and how glial cells contribute to this neurodegenerative disease remains to be elucidated. Because inflammatory treatments and products released from activated microglia increase glial hemichannel activity, we investigated whether amyloid-β peptide (Aβ) could regulate these channels in glial cells and affect neuronal viability. Microglia, astrocytes, or neuronal cultures as well as acute hippocampal slices made from GFAP-eGFP transgenic mice were treated with the active fragment of Aβ. Hemichannel activity was monitored by single-channel recordings and by time-lapse ethidium uptake, whereas neuronal death was assessed by Fluoro-Jade C staining. We report that low concentrations of Aβ25–35 increased hemichannel activity in all three cell types and microglia initiate these effects triggered by Aβ. Finally, neuronal damage occurs by activation of neuronal hemichannels induced by ATP and glutamate released from Aβ25–35-activated glia. These responses were observed in the presence of external calcium and were differently inhibited by hemichannel blockers, whereas the Aβ25–35-induced neuronal damage was importantly reduced in acute slices made from Cx43 knock-out mice. Thus, Aβ leads to a cascade of hemichannel activation in which microglia promote the release of glutamate and ATP through glial (microglia and astrocytes) hemichannels that induces neuronal death by triggering hemichannels in neurons. Consequently, this work opens novel avenues for alternative treatments that target glial cells and neurons to maintain neuronal survival in the presence of Aβ.