Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

Abstract

The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer’s disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-β peptide (Aβ). The morphological evaluation showed that Aβ treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aβ. Moreover, URB597 reduced both the increase of Rho protein activation in Aβ-treated BV-2 cells and the Aβ-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.

Phytocannabinoids and Cannabis-Based Products as Alternative Pharmacotherapy in Neurodegenerative Diseases: From Hypothesis to Clinical Practice

“…The ECS modulation has been studied as an alternative to AD treatment ( Mulder et al, 2011 ; Manuel et al, 2014 ). Preclinical studies performed in vitro and in vivo using synthetic drugs to modulate the ECS have already shown positive results regarding the reduction of Aβ plaque deposition and tau phosphorylation, improvement in the cognitive performance and reduction of glial activation and neuroinflammation ( Ramírez et al, 2005 ; Chen et al, 2011 , 2019 , 2012 ; Aso et al, 2012 ; Murphy et al, 2012 ; Zhang and Chen, 2018 ; Zhao et al, 2020 ; Grieco et al, 2021 ). On the other hand, the use of synthetic compounds, such as THC analogs, in clinical studies promoted an improvement only regarding aggressiveness and agitation in patients, not showing effectiveness in terms of primary symptoms of AD ( Passmore, 2008 ; Woodward et al, 2014 ; Herrmann et al, 2019 ).…”

Microglial Endocannabinoid Signalling in AD

“…Interestingly, the effects mentioned above were mediated neither by CB 1/2 receptors nor PPARs [ 123 ]. In the same cellular line, after Aβ peptide pro-inflammatory stimulation, FAAH inhibition was shown to decrease the release of pro-inflammatory cytokines, switching to the resting phenotype and reducing cell migration by modulating the Rho signalling pathway [ 124 ]. Moreover, URB597 also promoted the phagocytic activity of BV-2, by inducing a robust reorganization of the cytoskeleton [ 124 ].…”

“…In the same cellular line, after Aβ peptide pro-inflammatory stimulation, FAAH inhibition was shown to decrease the release of pro-inflammatory cytokines, switching to the resting phenotype and reducing cell migration by modulating the Rho signalling pathway [ 124 ]. Moreover, URB597 also promoted the phagocytic activity of BV-2, by inducing a robust reorganization of the cytoskeleton [ 124 ]. Unfortunately, the study did not investigate the receptors that were involved in this process, nor the underlying signalling cascades.…”

Macrophages: A communication network linking Porphyromonas gingivalis infection and associated systemic diseases

“…In peripheral circulation, macrophages are one of the pools for Ab (53), P. gingivalis activates the NF-kB/cathepsin B pathway, promoting the generation of Ab by macrophages (54), then peripheral Ab is transferred into the brain by advanced glycation end products (RAGE) expressed on cerebral endothelial cells (8). In vitro cell experiment confirmed that Ab could increase the expression of iNOS whereas it downregulated Arg-1 in microglia, inducing the M1 microglia (55).…”