Abstract

The mechanisms involved in Alzheimer’s disease (AD) are not completely understood and how glial cells contribute to this neurodegenerative disease remains to be elucidated. Recently we showed that amyloid-β peptide (Aβ) increase hemichannel activity in microglia, astrocytes and neurons, affecting neuronal viability. Because cannabinoids (CB) have anti-inflammatory properties and their receptors (CB-R) are largely expressed in microglia and astrocytes, we investigated upon primary glial cell cultures and hippocampal slices, the effects of CBs (WIN, 2-arachidonyglycerol, and methanandamide) on (i) Aβ-induced hemichannel activity in brain cells; (ii) Aβ-induced release of glutamate and ATP from glial cells and (iii) Aβ-induced neuronal death. Cultures of microglia, astrocytes or neurons as well as acute hippocampal slices were treated with 10 µM Aβ25-35 for 72 h or 3 h, respectively. Hemichannel activity was monitored by single channel recordings and by time-lapse ethidium uptake while neuronal death was assessed by Fluoro-Jade C staining. We found that WIN, 2-arachidonyglycerol and methanandamide strongly inhibited the Aβ25-35-induced hemichannel activity in glial cells, but not in neuronal cultures. Importantly, the Aβ25-35-induced release of glutamate and ATP via glial cell hemichannels was inhibited by CBs, reducing neuronal death. Pharmacological characterizations of the CBs actions on Aβ25-35-induced changes in glial hemichannel activity, glial glutamate/ATP release and neuronal revealed that these effects were mainly mediated through the CB1-R activation, although some partial action was observed via CB2-R activation. Altogether these data support the idea that under pro-inflammatory conditions, cannabinoids exert, through activation of different sub-types of glial CB-Rs, an inhibitory effect on glial hemichannel activity, which result neuroprotective and open novel avenues for alternative treatments for AD.