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Adenosine A_2A receptors (A_2AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ_1-42)-based model of early AD, we now unraveled that this involves an increased synaptic release of ATP coupled to an increased density and activity of ecto-5′-nucleotidase (CD73)-mediated formation of adenosine selectively activating A_2AR. Thus, CD73 inhibition with α,β-methylene-ADP impaired long-term potentiation (LTP) in mouse hippocampal slices, which is occluded upon previous superfusion with the A_2AR antagonist SCH58261. Furthermore, α,β-methylene-ADP did not alter LTP amplitude in global A_2AR knockout (KO) and in forebrain neuron-selective A_2AR-KO mice, but inhibited LTP amplitude in astrocyte-selective A_2AR-KO mice; this shows that CD73-derived adenosine solely acts on neuronal A_2AR. In agreement with the concept that ATP is a danger …