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Therefore, new pharmacological targets are being sought, such as elements of the endocannabinoid system (ECS). We analysed the occurrence of changes in the ECS in tauopathies and their implication in the pathogenesis. By integrating gene expression analysis, immunofluorescence, genetic and adeno-associated virus expressing TAU mouse models, we found a TAU-dependent increase in CB<jats:sub>2<\/jats:sub> receptor expression in hippocampal neurons, that occurs as an early event in the pathology and was maintained until late stages. These changes were accompanied by alterations in the endocannabinoid metabolism. Remarkably, CB<jats:sub>2<\/jats:sub> ablation in mice protects from neurodegeneration induced by hTAU<jats:sup>P301L<\/jats:sup> overexpression, corroborated at the level of cognitive behaviour, synaptic plasticity, and aggregates of insoluble TAU. At the level of neuroinflammation, the absence of CB<jats:sub>2<\/jats:sub> did not produce significant changes in concordance with a possible neuronal location rather than its classic glial expression in these models. These findings were corroborated in post-mortem samples of patients with Alzheimer\u2019s disease, the most common tauopathy. Our results show that neurons with accumulated TAU induce the expression of the CB<jats:sub>2<\/jats:sub> receptor, which enhances neurodegeneration. These results are important for our understanding of disease mechanisms, providing a novel therapeutic strategy to be investigated in tauopathies.<\/jats:p>","DOI":"10.1186\/s40478-021-01196-5","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T19:03:02Z","timestamp":1621278182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Cannabinoid receptor CB2 ablation protects against TAU induced neurodegeneration"],"prefix":"10.1186","volume":"9","author":[{"given":"M.","family":"Gal\u00e1n-Ganga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Rodr\u00edguez-Cueto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Merch\u00e1n-Rubira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"\u00c1vila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Posada-Ayala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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