title: A2A adenosine receptor deletion is protective in a mouse model of Tauopathy.
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.
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Laurent
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Burnouf
authors.affiliation: Inserm U1028-UMR 5292 CNRS-UCBL1, Centre of Research in Neurosciences, Lyon, France.
authors.forename: B
authors.identifier: http://orcid.org/0000-0001-5191-3035
authors.initials: B
authors.lastname: Ferry
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: V L
authors.initials: VL
authors.lastname: Batalha
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: J E
authors.initials: JE
authors.lastname: Coelho
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, University of Bonn, Bonn, Germany.|Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman.
authors.forename: Y
authors.initials: Y
authors.lastname: Baqi
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Malik
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.
authors.forename: E
authors.initials: E
authors.lastname: Mariciniak
authors.affiliation: Inserm U1028-UMR 5292 CNRS-UCBL1, Centre of Research in Neurosciences, Lyon, France.|NeuroDialyTics, Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: Parrot
authors.affiliation: Laboratory of Biological Psychology, Department of Psychology, KUL, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Van der Jeugd
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.
authors.forename: E
authors.initials: E
authors.lastname: Faivre
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.
authors.forename: V
authors.initials: V
authors.lastname: Flaten
authors.affiliation: IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Ledent
authors.affiliation: Laboratory of Biological Psychology, Department of Psychology, KUL, Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.|CHRU-Lille, Faculté de Médecine, Lille, France.
authors.forename: N
authors.initials: N
authors.lastname: Sergeant
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.|CHRU-Lille, Faculté de Médecine, Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Hamdane
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Humez
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
authors.forename: C E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors.forename: L V
authors.initials: LV
authors.lastname: Lopes
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.|CHRU-Lille, Faculté de Médecine, Lille, France.
authors.forename: L
authors.initials: L
authors.lastname: Buée
authors.affiliation: Université de Lille, UDSL, Lille, France.|Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.|CHRU-Lille, Faculté de Médecine, Lille, France.
authors.forename: D
authors.initials: D
authors.lastname: Blum
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008822:Mice, Transgenic; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D024801:Tauopathies / Q000188:drug therapy / Q000503:physiopathology*; D046509:Tissue Culture Techniques; D014970:Xanthines / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; C054369:MAPT protein, human; C113602:MSX 3 compound; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D014970:Xanthines; D016875:tau Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid