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P.66 NEURONAL ADENOSINE A2A RECEPTOR OVEREXPRESSION EXACERBATES TAU PATHOLOGY-ASSOCIATED MEMORY DEFICITS . E. Faivre 1 *, K. Carvalho 1 *, M. Pietrowski 2# , X. Marques 3# , V. Gomez-Murcia 1 , A. Deleau 1 , J. Hansen 2 , S. Kozlov 2 , C. Danis 1,7 , M. Temido-Ferreira 4 , J. E. Coelho 4 , C. Mériaux 1 , S. Eddarkaoui 1 , S. Le Gras 5 , M. Dumoulin 6 , L. Cellai 1 , NeuroCEB Brain Bank, I. Landrieu 7 , Y. Chern 8 , M. Hamdane 1 , L. Buée 1 , A. Boutillier 9 , S. Levi 3 , A. Halle 2,10 , L. V. Lopes 4 and D. Blum 1 1 . Univ. Lille, Inserm, CHU Lille, Lille, France. 2 . German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. 3 . Institut du Fer à Moulin, Paris, France. 4 . Instituto de Medicina Molecular, Lisbon, Portugal. 5 . Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Univ. de Strasbourg, Illkirch, France. 6 . Plateforme de ressources expérimentales, Univ. de Lille, Lille, France. 7 . Univ. Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France. 8 . Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. 9 . Laboratoire de Neuroscience Cognitives et Adaptatives, CNRS, Univ. de Strasbourg, Strasbourg, France. 10 . Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany * # equal contribution Tau pathology is defined by the accumulation of hyperphosphorylated and aggregated Tau protein in brain from patients suffering from neurodegenerative disorders known as tauopathies, including Alzheimer’s disease (AD) and Frontotemporal lobar degeneration (FTLD). In AD, the progression of Tau pathology corresponds to the progression of clinical symptoms, suggesting a central role in the development of cognitive deficits. However, pathways underlying Tau pathology– induced cognitive deficits remain ill-defined. Previous epidemiological and experimental studies pointed out that chronic caffeine consumption reduces AD risk and associated cognitive deficits. These protective effects were ascribed to the blockade of adenosine A 2A receptors (A 2A Rs), which are found upregulated in AD patient’s brains, notably at the neuronal level, in correlation with Tau pathology development and cognitive deficits. These observations suggest a link between A 2A R dysregulation, Tau pathology and memory in AD. Here, we evaluated the expression of A 2A R on human brain samples from FTLD patients with Tau mutation. We also developed a conditional model (Tet-Off) allowing A 2A R overexpression in CAMKII-positive neurons, crossed with THY-Tau22 mice, who develop a progressive hippocampal Tau pathology associated with cognitive decline. Animals were evaluated at 5-6 months of age, when pathology is expressed but not maximal. We demonstrated for the first time an association between neuronal upregulation of A 2A R and Tau pathology in the cortex of FTLD patients. Promoting neuronal A 2A R upregulation in a tauopathy mouse model led to a hippocampal upregulation of C1q associated with a loss of glutamatergic synapses and a potentiation of spatial memory deficits, suggesting an instrumental role of neuronal A 2A R dysregulation towards Tau pathology-induced synaptic loss and cognitive alterations. Altogether, these data suggest that neuronal A 2A R dysregulation seen in the brain of AD patients contributes to the development of Tau-induced cognitive impairments. Limiting A 2A R dysregulation may therefore represent a new therapeutic approach in AD and other tauopathies.