FAAH Inhibition as a Path to Mitigate Alzheimer's Disease Progression in Mouse Models of Amyloidosis
Oddi, S.; Scipioni, L.; Totaro, A.; Giacovazzo, G.; Ciaramellano, F.; Tortolani, D.; Leuti, A.; Businaro, R.; Armeli, F.; Bilkei-Gorzo, A.; Coccurello, R.; Zimmer, A.; Maccarrone, M.
Show abstract
The endocannabinoid N-arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimers disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis APP/PS1 and Tg2576. Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inactivation robustly suppressed {beta}-amyloid production and accumulation, associated with decreased expression of {beta}-site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1-dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis, and provide proof-of-concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD.
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