The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function

Vânia Batalha (1, 2) , Diana Ferreira (1, 3, 4) , Joana Coelho (1) , Jorge Valadas (1) , Rui Gomes (1) , Mariana Temido-Ferreira (1) , Tatiana Shmidt (5) , Younis Baqi (6, 7) , Luc Buée (8, 9) , Christa Müller (6) , Malika Hamdane (8, 9) , Tiago Outeiro (3, 10, 11) , Michael Bader (5, 12, 13) , Sebastiaan Meijsing (2) , Ghazaleh Sadri-Vakili (14) , David Blum (8, 9) , Luísa Lopes (1)

1 Universidade de Lisboa
2 MPIMG - Max Planck Institute for Molecular Genetics
3 UMG - University Medical Center Göttingen
4 Universidade do Porto = University of Porto
5 MDC - Max Delbrück Center for Molecular Medicine [Berlin]
6 Rheinische Friedrich-Wilhelms-Universität Bonn
7 SQU - Sultan Qaboos University
8 LilNCog - Lille Neurosciences & Cognition - U 1172
9 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
10 Max Planck Institute for Experimental Medicine [Göttingen, Germany]
11 CEDOC - Centro de Estudos de Doenças Crónicas
12 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
13 Universität zu Lübeck = University of Lübeck [Lübeck]
14 Massachusetts General Hospital [Boston]

Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer's and age-related cognitive impairments may rely on its ability to modulate GR actions.

Domaines: Neurosciences [q-bio.NC]

Vânia Batalha, Diana Ferreira, Joana Coelho, Jorge Valadas, Rui Gomes, et al.. The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function. Scientific Reports, 2016, 6, pp.31493. ⟨10.1038/srep31493⟩. ⟨inserm-01833352⟩