Anales RANF

P.63 NEURONAL ADENOSINE A 2A RECEPTOR OVEREXPRESSION EXACERBATES MEMORY DEFICITS IN THE APP/PS1 MOUSE MODEL OF ALZHEIMER’S DISEASE. V. Gomez-Murcia 1 , K. Carvalho 1* , C. Meriaux 1* , R. Caillierez 1 , M. Dumoulin 2 , S. Bégard 1 , M. Wisztorski 3 , I. Fournier 3 , N. Deglon 4 , A.P. Bemelmans 5,6 , M. Hamdane 1 , L. Buee 1 , E. Faivre 1 , D. Blum 1 . 1 Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, LabEx DISTALZ, F-59000 Lille, France. 2 Univ. Lille, F-59000 Lille, France. 3 Univ. Lille, Inserm, U1192-PRISM F-59000 Lille, France. 4 Department of Clinical Neurosciences, Laboratory of Neurotherapies and Neuromodulation (LNTM), Lausanne University Hospital, 1011 Lausanne, Switzerland; Neuroscience Research Center, LNTM, Lausanne University Hospital, 1011 Lausanne, Switzerland. 5 CEA, DRF, Institut François Jacob, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France. 6 CNRS, CEA, Paris-Sud Univ., Univ. Paris-Saclay, Neurodegenerative Diseases Laboratory (UMR9199), F-92265, Fontenay-aux-Roses, France. Epidemiological and experimental studies pointed-out that chronic caffeine consumption reduces Alzheimer's Disease (AD) risk and associated cognitive deficits. These protective effects are thought to be ascribed to the blockade of adenosine A 2A receptors (A 2A Rs). Interestingly, the latter are found abnormally upregulated in neurons of AD patient’s brains in correlation with the development of cognitive deficits. These observations suggest a link between neuronal A 2A R dysregulation and memory impairments in AD. To get insights towards this relationship, we aimed at evaluating the pathophysiological impact of a neuronal A 2A R upsurge in a transgenic model of AD- like amyloidogenesis (APP/PS1dE9 mice). To this aim, we crossed APP/PS1 mice with our newly developed transgenic TRE-A 2A strain, carrying the mouse A 2A R under the control of a Tet-responsive-element promoter. This led rise to four genotypic groups: WT, APP, WT/TRE-A 2A and APP/TRE-A 2A . At 3m of age, all the animals were bilaterally injected in the hippocampus with an AVV2/5-CBA-ttA allowing the preferential overexpression of ttA transactivator in neurons, allowing neuronal A 2A R upsurge in TRE animals. At 6m of age, a time APP mice do not display major deficits, behavioral evaluations revealed that, neuronal A 2A R overexpression strongly worsens spatial memory impairments of APP animals without significantly altering neither amyloid burden nor neuroinflammation. Using Mass spectrometry-based high- throughput proteomics, we identified modifications in the molecular profile of APP/TRE-A 2A as compared to APP mice. Gene ontology analysis revealed that proteins the most highly differentially expressed were related to synaptic function. Further experiments are now ongoing to get further insights into these synaptic dysfunctions. These data support that pathological upregulation of A 2A receptors in neurons is instrumental towards the decline of cognitive functions in AD. Fundings: Fondation pour la Recherche Médicale, Fondation Alzheimer, ANR, Inserm, Région Hauts de France, Université de Lille