Anales RANF

P.62 BENEFICIAL EFFECTS OF P2X7R DEFICIENCY IN A MOUSE MODEL OF TAUOPATHY K. Carvalho 1 , E. Martin 2 , A. Ces 2 , V. Sazdovitch 2 , A. Prigent 2 , B. Fontaine 3 , F. Sennlaub 4 , B. Delatour 2 , Buée L 1 , P. Dutar 5 , D. Blum 1 , C. Delarasse 2,4 1 Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, LabEx DISTALZ, F-59000 Lille, France ; 2 Sorbonne Université, INSERM, CNRS, Institut Cerveau et Moelle Epinière, Paris, France ; 3 Sorbonne Université, INSERM, CNRS, Institut de Myologie, Paris, France ; 4 Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France ; 5 Université Paris Sud, CNRS, Chatenay-Malabry, France. Alzheimer’s disease (AD) is characterized by two neuropathological lesions: the accumulation of amyloid peptides into plaques and of hyperphosphorylated Tau proteins into neurofibrillary tangles. The latter combined with neuroinflammatory reaction underline synaptic and cognitive deficits. P2X7 purinergic receptor was found abnormally upregulated in the AD brain, notably by glial cells. We recently demonstrated (Martin et al., Molecular Psychiatry, 2019) that amyloid pathology is prone to activate P2X7R and that its deletion rescues cognitive deficits and mitigated lesions in the APP/PS1 model of AD amyloïdogenesis. Protective effects of P2X7R deletion were ascribed to a reduction of CCL3 production and CD8 T-cells infiltration. In sharp contrast, the link between P2X7 and Tau pathology remains largely unknown. In the present study, we evaluated the role of P2X7R in a context of frontotemporal lobar degeneration (FTLD), a pure tauopathy using human tissue from FTLD patients with MAPT P301L mutation (FTLD-tau) and a mouse model based on FTLD-tau mutations (THY-Tau22), developing hippocampal Tau pathology along with plasticity and memory deficits. Our data demonstrate that P2X7R is upregulated in both the cortex of patients with FTLD-tau and the hippocampus of THY-Tau22 mice. Importantly, P2X7R deletion in THY-Tau22 mice improved long-term synaptic plasticity and hippocampal-dependent spatial memory. No major effect of P2X7R- deficiency on Tau phosphorylation were observed. However, lack of P2X7R improved the neuroinflammatory response by reducing microglia activation and related inflammatory markers. In conclusion, the present data are the first showing that P2X7R contributes to the pathological processes linked to the development of Tauopathy. Taken together, our findings support a detrimental role of P2X7R into the plasticity and memory deficits linked to the two AD lesions, paving the way towards P2X7R-based therapeutics in the context of AD patients.