Aβ 1-42 peptides blunt the adenosine A 2A receptor-mediated control of the interplay between P 2 X 7 and P 2 Y 1 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-β peptides (Aβ) 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 Ca 2+ 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 Aβ peptides affect ATP-mediated Ca 2+ responses in astrocytes measured by fluorescence live-cell imaging and whether A 2A R control astrocytic Ca 2+ responses mediated by ATP receptors, mainly P 2 X 7 R and P 2 Y 1 R. In primary cultures of rat astrocytes exposed to Aβ 1-42 , ATP-evoked Ca 2+ responses had a lower amplitude but a longer duration than in control astrocytes and involved P 2 X 7 R and P 2 Y 1 R, the former potentiating the later. Moreover, Aβ 1-42 exposure increased protein levels of P 2 Y 1 R in astrocytes. A 2A R antagonism with SCH58261 controlled in a protein kinase A-dependent manner both P 2 X 7 R- and P 2 Y 1 R-mediated Ca 2+ responses in astrocytes. The interplay between these purinoceptors in astrocytes was blunted upon exposure to Aβ 1-42 . These findings uncover the ability of A 2A R to regulate the inter-twinned P 2 X 7 R- and P 2 Y 1 R-mediated Ca 2+ dynamics in astrocytes, which is disrupted in conditions of early AD.