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_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 signal in the brain, ATP release from nerve terminals is increased after intracerebroventricular Aβ_1-42 administration, together with CD73 and A_2AR upregulation in hippocampal synapses. Importantly, this increased CD73 activity is critically required for Aβ_1-42 to impair synaptic plasticity and memory since Aβ_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_2AR and imply CD73 as a novel target for modulation of early AD.

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