Expression of the Adenosine A(2A)-A(3) Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APP(Sw,Ind) Alzheimer's Disease Model

Adenosine (Ado) receptors have been instrumental in the detection of heteromers and other higher-order receptor structures, mainly via interactions with other cell surface G-protein-coupled receptors. Apart from the first report of the A(1) Ado receptor interacting with the A(2A) Ado receptor, there has been more recent data on the possibility that every Ado receptor type, A(1), A(2A), A(2B), and A(3), may interact with each other. The aim of this paper was to look for the expression and function of the A(2A)/A(3) receptor heteromer (A(2A)A(3)Het) in neurons and microglia. In situ proximity ligation assays (PLA), performed in primary cells, showed that A(2A)A(3)Het expression was markedly higher in striatal than in cortical and hippocampal neurons, whereas it was similar in resting and activated microglia. Signaling assays demonstrated that the effect of the A(2A)R agonist, PSB 777, was reduced in the presence of the A(3)R agonist, 2-Cl-IB-MECA, whereas the effect of the A(3)R agonist was potentiated by the A(2A)R antagonist, SCH 58261. Interestingly, the expression of the heteromer was markedly enhanced in microglia from the APP(Sw,Ind) model of Alzheimer's disease. The functionality of the heteromer in primary microglia from APP(Sw,Ind) mice was more similar to that found in resting microglia from control mice.