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Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with A\u03b225-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers\u2019 modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1\/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR\/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD.<\/jats:p>","DOI":"10.3390\/ijms252212044","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T03:52:07Z","timestamp":1731297127000},"page":"12044","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4981-3374","authenticated-orcid":false,"given":"Federica","family":"Armeli","sequence":"first","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7059-7015","authenticated-orcid":false,"given":"Roberto","family":"Coccurello","sequence":"additional","affiliation":[{"name":"European Brain Research Center, Santa Lucia Foundation IRCCS, 00143 Rome, Italy"},{"name":"Institute for Complex Systems (ISC), National Research Council (C.N.R.), 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Giacovazzo","sequence":"additional","affiliation":[{"name":"European Brain Research Center, Santa Lucia Foundation IRCCS, 00143 Rome, Italy"},{"name":"School of Veterinary Medicine, University of Teramo (UniTE), 64100 Teramo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5245-1684","authenticated-orcid":false,"given":"Beatrice","family":"Mengoni","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Paoletti","sequence":"additional","affiliation":[{"name":"European Brain Research Center, Santa Lucia Foundation IRCCS, 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6217-698X","authenticated-orcid":false,"given":"Sergio","family":"Oddi","sequence":"additional","affiliation":[{"name":"European Brain Research Center, Santa Lucia Foundation IRCCS, 00143 Rome, Italy"},{"name":"School of Veterinary Medicine, University of Teramo (UniTE), 64100 Teramo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3990-2963","authenticated-orcid":false,"given":"Mauro","family":"Maccarrone","sequence":"additional","affiliation":[{"name":"European Brain Research Center, Santa Lucia Foundation IRCCS, 00143 Rome, Italy"},{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7890-8524","authenticated-orcid":false,"given":"Rita","family":"Businaro","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1124\/pharmrev.122.000600","article-title":"Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years","volume":"75","author":"Maccarrone","year":"2023","journal-title":"Pharmacol. 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