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

Batalha, V., Ferreira, D. G., Coelho, J. E., Valadas, J. S., Gomes, R., Temido-Ferreira, M., et al. (2016). The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function. Scientific Reports, 6: 31493. doi:10.1038/srep31493.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-46C1-5 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-46C2-3
Genre: Journal Article

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 Creators:
Batalha, Vania1, Author              
Ferreira, Diana G., Author
Coelho, Joana E., Author
Valadas, Jorge S., Author
Gomes, Rui, Author
Temido-Ferreira, Mariana, Author
Shmidt, Tatiana, Author
Baqi, Younis, Author
Buée, Luc, Author
Müller, Christa E., Author
Hamdane, Malika, Author
Outeiro, Tiago Fleming, Author
Bader, Michael, Author
Meijsing, Sebastiaan1, Author              
Sadri-Vakili, Ghazaleh, Author
Blum, David, Author
Lopes, Luísa V., Author
Affiliations:
1Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479641              

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 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.

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Language(s): eng - English
 Dates: 2016-08-11
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/srep31493
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Title: Scientific Reports
  Abbreviation : Sci. Rep.
Source Genre: Journal
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Publ. Info: London, UK : Nature Publishing Group
Pages: - Volume / Issue: 6 Sequence Number: 31493 Start / End Page: - Identifier: ISSN: 2045-2322
CoNE: /journals/resource/2045-2322