Aβ1-42 peptides blunt the adenosine A2A receptor-mediated control of the interplay between P2X7 and P2Y1 receptors mediated calcium responses in astrocytes

The contribution of astrocytes to Alzheimer's disease (AD) is still ill defined. AD involves an abnormal accumulation of amyloid-beta peptides (A beta) and increased production of danger signals such as ATP. ATP can direct or indirectly, through its metabolism into adenosine, trigger adaptive astrocytic responses resulting from intracellular Ca2+ oscillations. AD also triggers an upregulation of astrocytic adenosine A(2A) receptors (A(2A)R), which blockade prevents memory dysfunction in AD. We now investigated how A beta peptides affect ATP-mediated Ca2+ responses in astrocytes measured by fluorescence live-cell imaging and whether A(2A)R control astrocytic Ca2+ responses mediated by ATP receptors, mainly P2X7R and P2Y1R. In primary cultures of rat astrocytes exposed to A beta(1-42), ATP-evoked Ca2+ responses had a lower amplitude but a longer duration than in control astrocytes and involved P2X7R and P2Y1R, the former potentiating the later. Moreover, A beta(1-42) exposure increased protein levels of P2Y1R in astrocytes. A(2A)R antagonism with SCH58261 controlled in a protein kinase A-dependent manner both P2X7R- and P2Y1R-mediated Ca2+ responses in astrocytes. The interplay between these purinoceptors in astrocytes was blunted upon exposure to A beta(1-42). These findings uncover the ability of A(2A)R to regulate the inter-twinned P2X7R- and P2Y1R-mediated Ca2+ dynamics in astrocytes, which is disrupted in conditions of early AD.