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Mol Psychiatry. 2016 Jan;21(1):97-107. doi: 10.1038/mp.2014.151. Epub 2014 Dec 2.

A2A adenosine receptor deletion is protective in a mouse model of Tauopathy.

Author information

1
Université de Lille, UDSL, Lille, France.
2
Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.
3
Inserm U1028-UMR 5292 CNRS-UCBL1, Centre of Research in Neurosciences, Lyon, France.
4
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
5
PharmaCenter Bonn, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
6
Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman.
7
NeuroDialyTics, Lyon, France.
8
Laboratory of Biological Psychology, Department of Psychology, KUL, Leuven, Belgium.
9
IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
10
CHRU-Lille, Faculté de Médecine, Lille, France.

Abstract

Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.

PMID:
25450226
DOI:
10.1038/mp.2014.151
[Indexed for MEDLINE]

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