Adenosine A2A Receptor Antagonists Affects NMDA Glutamate Receptor Function. Potential to Address Neurodegeneration in Alzheimer's Disease
Franco, Rafael (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Rivas-Santisteban, Rafael (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Casanovas, Mireia (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Lillo, Alejandro (Universitat de Barcelona. Departament de Bioquímica i Fisiologia)
Saura Antolín, Carlos (Universitat Autònoma de Barcelona. Institut de Neurociències)
Navarro Brugal, Gemma (Universitat de Barcelona. Departament de Bioquímica i Fisiologia)
Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular

Date:	2020
Abstract:	(1) Background. N-methyl d-aspartate (NMDA) ionotropic glutamate receptor (NMDAR), which is one of the main targets to combat Alzheimer's disease (AD), is expressed in both neurons and glial cells. The aim of this paper was to assess whether the adenosine A2A receptor (A2AR), which is a target in neurodegeneration, may affect NMDAR functionality. (2) Methods. Immuno-histo/cytochemical, biophysical, biochemical and signaling assays were performed in a heterologous cell expression system and in primary cultures of neurons and microglia (resting and activated) from control and the APPSw,Ind transgenic mice. (3) Results. On the one hand, NMDA and A2A receptors were able to physically interact forming complexes, mainly in microglia. Furthermore, the amount of complexes was markedly enhanced in activated microglia. On the other hand, the interaction resulted in a novel functional entity that displayed a cross-antagonism, that could be useful to prevent the exacerbation of NMDAR function by using A2AR antagonists. Interestingly, the amount of complexes was markedly higher in the hippocampal cells from the APPSw,Ind than from the control mice. In neurons, the number of complexes was lesser, probably due to NMDAR not interacting with the A2AR. However, the activation of the A2AR receptors resulted in higher NMDAR functionality in neurons, probably by indirect mechanisms. (4) Conclusions. A2AR antagonists such as istradefylline, which is already approved for Parkinson's disease (Nouriast® in Japan and Nourianz® in the US), have potential to afford neuroprotection in AD in a synergistic-like fashion. i. e. , via both neurons and microglia.
Grants:	Ministerio de Economía y Competitividad BFU2015-64405-R Agencia Estatal de Investigación SAF2016-80027-R Agencia Estatal de Investigación SAF2017-84117-R Agencia Estatal de Investigación PID2019-109240RB-I00 Agencia Estatal de Investigación RTI2018-094204-B-I00
Note:	Altres ajuts: This work was partially supported by the AARFD-17-503612 grant from the US Alzheimer's Association.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	G-protein-coupled receptors ; Functional selectivity ; Microglia ; Neuroprotection ; Cognition ; Signaling
Published in:	Cells, Vol. 9 Núm. 5 (april 2020) , ISSN 2073-4409

DOI: 10.3390/cells9051075
PMID: 32357548

16 p, 2.7 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles