Anales RANF

S3-01 INVOLVEMENT OF PURINERGIC P2X4 RECEPTORS IN ALZHEIMER DISEASE Hua J., Garcia de Paco E., Rassendren F., Ulmann L. Institut de Génomique Fonctionnelle - Labex ICST - CNRS UMR 5203 - INSERM U1191 - Université de Montpellier, Montpellier, France P2X4 receptors (P2X4R) are ATP-gated ion channels involved in several inflammatory processes and are expressed de novo in reactive microglia, the resident macrophages of the CNS, during neuroinflammation. In light of this, we investigated the implication of microglial P2X4R in Alzheimer disease that is characterized by neurofibrillary tangles, amyloid deposits and chronic inflammation. Using APP/PS1 and APP/PS1xP2X4 -/- mice, we demonstrate that mice lacking P2X4R present better mnesic performances, associated with a lower level of soluble amyloid peptide. Immunostainings show that P2X4R are highly expressed in reactive microglia surrounding amyloid deposits in cortex and hippocampus and strongly co-localize with ApoE, a well-known risk factor for Alzheimer disease. Moreover, using proteomic studies, we found that P2X4 and ApoE interact and that the level of secreted ApoE is strongly increased in P2X4R -/- microglia. Interestingly, we also show that cathepsin B, a lysosomal enzyme, is not active in P2X4 -/- microglia, leading to the increase of ApoE concentration. These results indicate that P2X4, by modulating enzymatic degradation of ApoE in reactive microglia, play crucial role in Alzheimer disease.