title: The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.
abstract: 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.
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal.|Max Planck Institute for Molecular Genetics, Berlin,Germany.
authors: Vânia L
authors: VL
authors: Batalha
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal.|Department of NeuroDegeneration and Restorative Research, University Medical Center Goettingen, Waldweg 33, 37073 Göttingen, Germany.|Instituto de Farmacologia e Terapêutica, Faculdade de Medicina do Porto, Universidade do Porto, Portugal.
authors: Diana G
authors: DG
authors: Ferreira
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal.
authors: Joana E
authors: JE
authors: Coelho
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal.
authors: Jorge S
authors: JS
authors: Valadas
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal.|Faculdade de Ciências de Lisboa, Universidade de Lisboa, Portugal.
authors: Rui
authors: R
authors: Gomes
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal.
authors: Mariana
authors: M
authors: Temido-Ferreira
authors: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors: Tatiana
authors: T
authors: Shmidt
authors: PharmaCenter Bonn, Pharmazeutische Chemie I, Pharmazeutisches Institut, University of Bonn, Bonn, Germany.|Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman.
authors: Younis
authors: Y
authors: Baqi
authors: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, Alzheimer &Tauopathies, Lille, France.
authors: Luc
authors: L
authors: Buée
authors: PharmaCenter Bonn, Pharmazeutische Chemie I, Pharmazeutisches Institut, University of Bonn, Bonn, Germany.
authors: Christa E
authors: CE
authors: Müller
authors: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, Alzheimer &Tauopathies, Lille, France.
authors: Malika
authors: M
authors: Hamdane
authors: Department of NeuroDegeneration and Restorative Research, University Medical Center Goettingen, Waldweg 33, 37073 Göttingen, Germany.|Max Planck Institute for Experimental Medicine, Goettingen, Germany.|CEDOC, Centro de Estudos de Doenças Crónicas, Lisbon, Portugal.
authors: Tiago F
authors: TF
authors: Outeiro
authors: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.|Charité-University Medicine Berlin, Germany.|Institute of Biology, University of Lübeck, Germany.
authors: Michael
authors: M
authors: Bader
authors: Max Planck Institute for Molecular Genetics, Berlin,Germany.
authors: Sebastiaan H
authors: SH
authors: Meijsing
authors: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, United States of America.
authors: Ghazaleh
authors: G
authors: Sadri-Vakili
authors: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, Alzheimer &Tauopathies, Lille, France.
authors: David
authors: D
authors: Blum
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal.
authors: Luísa V
authors: LV
authors: Lopes
mesh_terms: D000375:Aging / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002110:Caffeine / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008822:Mice, Transgenic; D023421:Models, Animal; D009473:Neuronal Plasticity; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: C000627179:ADORA2A protein, human; D043705:Receptor, Adenosine A2A; D011965:Receptors, Glucocorticoid; D002110:Caffeine; D003345:Corticosterone