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

Francisco Q. Gonçalves, João P. Lopes, Henrique B. Silva, Cristina Lemos, António C. Silva, Nélio Gonçalves, Ângelo R. Tomé, Samira G. Ferreira, Paula M. Canas, Daniel Rial, Paula Agostinho, Rodrigo A. Cunha
Neurobiology of Disease. 2019-12-01; 132: 104570
DOI: 10.1016/j.nbd.2019.104570

PubMed
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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 activity is critically required for Aβ1-42 to
impair synaptic plasticity and memory since Aβ1-42-induced synaptic and memory
deficits were eliminated in CD73-KO mice. These observations establish a key
regulatory role of CD73 activity over neuronal A2AR and imply CD73 as a novel
target for modulation of early AD.

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