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Microglial cells play an important function in the inflammatory response; specifically, the emergence of disease\u2010associated microglia (DAM) has offered new insights into the conflicting perspectives on the detrimental or beneficial roles of microglia. We previously showed that modulating the endocannabinoid tone by fatty acid amide hydrolase (FAAH) inactivation renders beneficial effects in an amyloidosis context, paradoxically accompanied by an exacerbated neuroinflammatory response and the enrichment of DAM population. Here, we aim to elucidate the role of microglial cells in FAAH\u2010lacking mice in the 5xFAD mouse model of AD by using RNA\u2010sequencing analysis, molecular determinations, and morphological studies by using in vivo multiphoton microscopy. FAAH\u2010lacking AD mice displayed upregulated inflammatory genes and exhibited a DAM genetic profile. Conversely, genes linked to AD were downregulated. Depleting microglia using PLX5622 revealed that plaque\u2010associated microglia in FAAH\u2010deficient AD mice had a more stable, ramified morphology and increased A\u03b2 uptake, leading to reduced plaque growth compared to control mice. Importantly, FAAH expression was negligible in microglial cells, thus suggesting a role for FAAH in the cellular interplay in the central nervous system. Our findings show that\n                    <jats:italic>Faah<\/jats:italic>\n                    gene inactivation triggers a hetero\u2010cellular enhancement of microglial function that was paradoxically paralleled by an exacerbated inflammatory response. Taken together, the present data highlight FAAH as a potential therapeutic target in AD.\n                  <\/jats:p>","DOI":"10.1002\/glia.24638","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T11:37:45Z","timestamp":1730288265000},"page":"352-367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Fatty acid amide hydrolase gene inactivation induces hetero\u2010cellular potentiation of microglial function in the\n                    <scp>5xFAD<\/scp>\n                    mouse model of Alzheimer's disease"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5940-3301","authenticated-orcid":false,"given":"Mar\u00eda Andrea","family":"Arnanz","sequence":"first","affiliation":[{"name":"Faculty of Experimental Sciences Universidad Francisco de Vitoria  Madrid 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Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin F.","family":"Cravatt","sequence":"additional","affiliation":[{"name":"The Skaggs Institute for Chemical Biology, Department of Cell Biology The Scripps Research Institute  San Diego California USA"},{"name":"The Skaggs Institute for Chemical Biology, Department of Chemistry The Scripps Research Institute  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5379-0080","authenticated-orcid":false,"given":"Ricardo","family":"Mostany","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Tulane University School of Medicine  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor Javier S\u00e1nchez\u2010Ar\u00e9valo","family":"Lobo","sequence":"additional","affiliation":[{"name":"Faculty of Experimental Sciences Universidad Francisco de Vitoria  Madrid 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