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

Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiol Dis. 2019 Aug 05;:104570 Authors: Gonçalves FQ, Lopes JP, Silva HB, Lemos C, Silva AC, Gonçalves N, Tomé ÂR, Ferreira SG, Canas PM, Rial D, Agostinho P, Cunha RA Abstract Adenosine A2A receptors (A2AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ1-42)-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 A2AR. 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 A2AR antagonist SCH58261. Furthermore, α,β-methylene-ADP did not alter LTP amplitude in global A2AR knockout (KO) and in forebrain neuron-selective A2AR-KO mice, but inhibited LTP amplitude in astrocyte-selective A2AR-KO mice; this shows that CD73-derived adenosine solely acts on neuronal A2AR. In agreement with the concept that ATP is a danger signal in the brain, ATP release from nerve terminals is increased after intracerebroventricular Aβ1-42 administration, together with CD73 and A2AR upregulation in hippocampal synapses. Importantly, this increased CD73 act...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research