[en] Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) and mitigates both amyloid and Tau lesions in transgenic mouse models of the disease. While short-term treatment with A2AR antagonists have been shown to alleviate cognitive deficits in mouse models of amyloidogenesis, impact of a chronic and long-term treatment on the development of amyloid burden, associated neuroinflammation and memory deficits has never been assessed. In the present study, we have evaluated the effect of a 6-month treatment of APPsw/PS1dE9 mice with the potent and selective A2AR antagonist MSX-3 from 3 to 9-10 months of age. At completion of the treatment, we found that the MSX-3 treatment prevented the development of memory deficits in APP/PS1dE9 mice, without significantly altering hippocampal and cortical gene expressions. Interestingly, MSX-3 treatment led to a significant decrease of Aβ1-42 levels in the cortex of APP/PS1dE9 animals, while Aβ1-40 increased, thereby strongly affecting the Aβ1-42/Aβ1-40 ratio. Together, these data support the idea that A2AR blockade is of therapeutic value for AD.
Disciplines :
Neurology
Author, co-author :
Faivre, Emilie; Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert Research Centre UMR-S1172, Alzheimer & Tauopathies, Lille, France
Coelho, Joana E; Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisbon, Portugal
Zornbach, Katja; Center of Advanced European Studies and Research, Bonn, Germany
Malik, Enas; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany
Baqi, Younis; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany ; Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman
Schneider, Marion; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany
Cellai, Lucrezia; Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert Research Centre UMR-S1172, Alzheimer & Tauopathies, Lille, France
Carvalho, Kevin; Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert Research Centre UMR-S1172, Alzheimer & Tauopathies, Lille, France
Sebda, Shéhérazade; Plateau de Génomique Fonctionnelle et Structurale, CHU Lille, University of Lille, Lille, France
Figeac, Martin; Plateau de Génomique Fonctionnelle et Structurale, CHU Lille, University of Lille, Lille, France
Eddarkaoui, Sabiha; Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert Research Centre UMR-S1172, Alzheimer & Tauopathies, Lille, France
Caillierez, Raphaëlle; Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert Research Centre UMR-S1172, Alzheimer & Tauopathies, Lille, France
Chern, Yijuang; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
HENEKA, Michael ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Neurodegenerative Diseases and Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany
Sergeant, Nicolas; Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert Research Centre UMR-S1172, Alzheimer & Tauopathies, Lille, France
Müller, Christa E; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany
Halle, Annett; Center of Advanced European Studies and Research, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Buée, Luc; Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert Research Centre UMR-S1172, Alzheimer & Tauopathies, Lille, France
Lopes, Luisa V; Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisbon, Portugal
Blum, David; Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert Research Centre UMR-S1172, Alzheimer & Tauopathies, Lille, France
This work was supported by a cross-border grant from LECMA/Alzheimer Forschung Initiative/Vaincre Alzheimer (to DB and CM). We hereby thank Frédéric Leprêtre for submitting transcriptomics data to GEO. EF and KC are supported by Université de Lille, LC was supported by Italian Society of Pharmacology and LabEx DISTALZ.
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