Fatty acid amide hydrolase gene inactivation induces hetero‐cellular potentiation of microglial function in the 5xFAD mouse model of Alzheimer's disease

Neuroinflammation has recently emerged as a crucial factor in Alzheimer's disease (AD) etiopathogenesis. Microglial cells play an important function in the inflammatory response; specifically, the emergence of disease‐associated 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‐lacking mice in the 5xFAD mouse model of AD by using RNA‐sequencing analysis, molecular determinations, and morphological studies by using in vivo multiphoton microscopy. FAAH‐lacking 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‐associated microglia in FAAH‐deficient AD mice had a more stable, ramified morphology and increased Aβ 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 Faah gene inactivation triggers a hetero‐cellular 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. Main Points 5xFAD/FAAH−/− mice exhibit upregulated inflammatory genes, DAM profile, and downregulated AD‐linked genes. Microglia in 5xFAD/FAAH−/− mice have ramified morphology and increased Aβ uptake. FAAH inactivation enhances microglial function in 5xFAD.