Fatty-acid amide hydrolase inhibition mitigates Alzheimer's disease progression in mouse models of amyloidosis

• Published in: The FEBS journal 2025-01
• Main Authors: Oddi, Sergio, Scipioni, Lucia, Totaro, Antonio, Giacovazzo, Giacomo, Ciaramellano, Francesca, Tortolani, Daniel, Leuti, Alessandro, Businaro, Rita, Armeli, Federica, Bilkei-Gorzo, Andras, Coccurello, Roberto, Zimmer, Andreas, Maccarrone, Mauro
• Format: Article
• Language: English
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17403

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 Alzheimer's 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 inhibition robustly suppressed β-amyloid production and accumulation, associated with decreased expression of β-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.