| First Author | Gonçalves FQ | Year | 2019 |
| Journal | Neurobiol Dis | Volume | 132 |
| Pages | 104570 | PubMed ID | 31394204 |
| Mgi Jnum | J:293666 | Mgi Id | MGI:6453251 |
| Doi | 10.1016/j.nbd.2019.104570 | Citation | Goncalves FQ, et al. (2019) Synaptic and memory dysfunction in a beta-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiol Dis 132:104570 |
| abstractText | Adenosine A2A receptors (A2AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a beta-amyloid (Abeta1-42)-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 alpha,beta-methylene-ADP impaired long-term potentiation (LTP) in mouse hippocampal slices, which is occluded upon previous superfusion with the A2AR antagonist SCH58261. Furthermore, alpha,beta-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 Abeta1-42 administration, together with CD73 and A2AR upregulation in hippocampal synapses. Importantly, this increased CD73 activity is critically required for Abeta1-42 to impair synaptic plasticity and memory since Abeta1-42-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. |
