title: Amyloid β-induced death in neurons involves glial and neuronal hemichannels.
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 Aβ(25-35) 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 Aβ(25-35)-activated glia. These responses were observed in the presence of external calcium and were differently inhibited by hemichannel blockers, whereas the Aβ(25-35)-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.
authors: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago 6513677, Chile. jaorella@uc.cl
authors: Juan A
authors: JA
authors: Orellana
authors: Kenji F
authors: KF
authors: Shoji
authors: Verónica
authors: V
authors: Abudara
authors: Pascal
authors: P
authors: Ezan
authors: Edwige
authors: E
authors: Amigou
authors: Pablo J
authors: PJ
authors: Sáez
authors: Jean X
authors: JX
authors: Jiang
authors: Christian C
authors: CC
authors: Naus
authors: Juan C
authors: JC
authors: Sáez
authors: Christian
authors: C
authors: Giaume
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D018031:Connexin 43; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D018698:Glutamic Acid; D000255:Adenosine Triphosphate