Abstract

Alzheimer disease (AD) is an age-dependent neurodegenerative disorder characterized clinically by progressive loss of cognitive function and memory. The extracellular deposition of amyloid-β peptide (Aβ) in senile plaques is a common feature of this disease. Nevertheless, the mechanism of action of A is not completely understood. Because inflammatory conditions increase the opening probability of astroglial hemichannels formed by connexin43, we investigated whether Aβ25-35 could affect the astroglial hemichannel activity and neuronal viability in acute brain slices. For that purpose, acute hippocampal brain slices obtained from GFAP-EGFP transgenic mice were treated for 3 h with 10 µM Aβ25-35 alone or in the presence of the cannabinoids: WIN 55,212-2 (WIN, 5 µM), 2-arachinonylglycerol (2-AG, 5 µM) or methanandamine (Meth, 5 µM). Then, astroglial hemichannel activity and neuronal death were evaluated by ethidium (Etd) uptake and Fluoro-Jade C positive cells, respectively. Aβ25-35 increased Etd uptake in astrocytes (350%) and neurons (450%) compared to control slices and this response was completely inhibited by connexin and pannexin hemichannel blockers, respectively. Moreover, Aβ25-35 did not increase astroglial hemichannel activity in slices from connexin 43 knock-out mice. In addition, Aβ25-35 induced neuronal death of piramydal neurons, which was prevented with connexin and pannexin hemichannel blockers. All Aβ25-35 effects on astroglial hemichannel activity and neuronal death were blocked with the co-incubation of cannabinoids: WIN, 2-AG or Meth. Thus, connexin43 hemichannels may be a novel therapeutic target to reduce neuronal death during AD.