Expression of the Adenosine A2A-A3 Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APPSw,Ind Alzheimer's Disease Model

Alejandro Lillo; Iu Raïch; Jaume Lillo; Catalina Pérez-Olives; Gemma Navarro; Rafael Franco

doi:10.3390/biomedicines10020214

Expression of the Adenosine A_2A-A₃ Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APP_Sw,Ind Alzheimer's Disease Model

Biomedicines. 2022 Jan 19;10(2):214. doi: 10.3390/biomedicines10020214.

Authors

Alejandro Lillo^{1

2}, Iu Raïch^{1

2}, Jaume Lillo^{1

3}, Catalina Pérez-Olives^{1

3}, Gemma Navarro^{1

2

4}, Rafael Franco^{1

3

5

6}

Affiliations

¹ Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CiberNed), National Institute of Health Carlos III, Valderrebollo 5, 28031 Madrid, Spain.
² Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain.
³ Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
⁴ Institut de Neurociències, Universitat de Barcelona (UBNeuro), 08036 Barcelona, Spain.
⁵ School of Chemistry, University of Barcelona, 08028 Barcelona, Spain.
⁶ Faculty of Biology, Universitat de Barcelona, Diagonal 643, Prevosti Building, 08028 Barcelona, Spain.

Abstract

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 A₁ Ado receptor interacting with the A_2A Ado receptor, there has been more recent data on the possibility that every Ado receptor type, A₁, A_2A, A_2B, and A₃, may interact with each other. The aim of this paper was to look for the expression and function of the A_2A/A₃ receptor heteromer (A_2AA₃Het) in neurons and microglia. In situ proximity ligation assays (PLA), performed in primary cells, showed that A_2AA₃Het 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_2AR agonist, PSB 777, was reduced in the presence of the A₃R agonist, 2-Cl-IB-MECA, whereas the effect of the A₃R agonist was potentiated by the A_2AR 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.

Keywords: G protein-coupled receptor; activated microglia; cerebral cortex; dementia; hippocampus; neurodegenerative disease; neuroinflammation; purinergic signaling; striatum.

Abstract

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