Amyloid β-induced death in neurons involves glial and neuronal hemichannels

Juan A. Orellana, Kenji F. Shoji, Verónica Abudara, Pascal Ezan, Edwige Amigou, Pablo J. Sáez, Jean X. Jiang, Christian C. Naus, Juan C. Sáez, Christian Giaume

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

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 theAβ25-35-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.

Original languageEnglish (US)
Pages (from-to)4962-4977
Number of pages16
JournalJournal of Neuroscience
Volume31
Issue number13
DOIs
StatePublished - Mar 30 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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