Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine

Adenosine A(2A) receptors (A(2A)R) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a beta-amyloid (A beta(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(2A)R. Thus, CD73 inhibition with alpha,beta-methylene-ADP impaired long-term potentiation (LTP) in mouse hippocampal slices, which is occluded upon previous superfusion with the A(2A)R antagonist SCH58261. Furthermore, alpha,beta-methylene-ADP did not alter LTP amplitude in global A(2A)R knockout (KO) and in forebrain neuron-selective A(2A)R-KO mice, but inhibited LIT amplitude in astrocyte-selective A(2A)R-KO mice; this shows that CD73-derived adenosine solely acts on neuronal A(2A)R. In agreement with the concept that ATP is a danger signal in the brain, ATP release from nerve terminals is increased after intracerebroventricular beta(1-42) administration, together with CD73 and A(2A)R upregulation in hippocampal synapses. Importantly, this increased CD73 activity is critically required for A beta(1-42) to impair synaptic plasticity and memory since A beta(1-42)-induced synaptic and memory deficits were eliminated in CD73-KO mice. These observations establish a key regulatory role of CD73 activity over neuronal A(2A)R and imply CD73 as a novel target for modulation of early