Amyloid β-Induced Death in Neurons Involves Glial and Neuronal Hemichannels

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 hemi-channel activity, we investigated whether amyloid-beta peptide (A beta) 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 A beta. 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 A beta(25-35) increased hemichannel activity in all three cell types and microglia initiate these effects triggered by A beta. Finally, neuronal damage occurs by activation of neuronal hemichannels induced by ATP and glutamate released from A beta(25-35)-activated glia. These responses were observed in the presence of external calcium and were differently inhibited by hemichannel blockers, whereas the A beta(25-35)-induced neuronal damage was importantly reduced in acute slices made from Cx43 knock-out mice. Thus, A beta 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 A beta.