Background: Neuroinflammation has recently emerged as a crucial factor in Alzheimer Disease (AD) etiopathogenesis. However, its specific role in neurodegenerative diseases is still controversial. 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 have previously shown that the modulation of the endocannabinoid tone by fatty acid amide hydrolase (FAAH) inactivation renders beneficial effects in a context of amyloidosis, which were paradoxically triggered by an exacerbated neuroinflammatory response and the presence of a DAM enriched microglial population.
Methods: In the present work, we performed an RNA sequencing analysis, molecular determinations and morphological studies by using in vivo multiphoton microscopy to gain a deeper understanding of the role of microglial cells in FAAH lacking mice in the 5xFAD mouse model of AD.
Results: FAAH lacking AD mice showed an upregulation of genes involved in various inflammatory signalling pathways and exhibited a DAM genetic profile, whereas the expression of genes associated with AD was downregulated, as revealed by gene set enrichment analysis (GSEA). Furthermore, 28 days of pharmacological ablation of microglia induced by a specific CSF1R antagonist (PLX5622) allowed us to observe that plaque associated, but not non associated, microglial cells in 5xFAD null FAAH mice, exhibited a more stable morphological profile (including longer, more ramifiedand less spherical processes) and an enhanced uptake of AB peptides, along with reduced growth of amyloid plaques, as compared to those observed in 5xFAD mice. Importantly, FAAH expression was negligible in microglial cells, thus suggesting a role for FAAH in the cellular interplay in the CNS.
Conclusions: Our findings show that FAAH gene inactivation triggers a heterocellular 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. Less...