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

• DOI: 10.1111/febs.17403
• Publication Date: 2025-01-17T06:52:47Z
• Authors: Sergio Oddi; Lucia Scipioni; Antonio Totaro; Giacomo Giacovazzo; Francesca Ciarame...; Daniel Tortolani; Alessandro Leuti; Rita Businaro; Federica Armeli; Andras Bilkei‐Gorzo; Roberto Coccurello; Andreas Zimmer; Mauro Maccarrone
• Keywords: Amyloid (mycology); Hydrolase; Amide

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), major enzyme degrading AEA, in mouse models amyloidosis (APP/PS1 Tg2576). Enhancing AEA signaling by genetic deletion FAAH delayed cognitive deficits APP/PS1 mice improved symptoms 12‐month‐old AD‐like mice. Chronic pharmacological inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, promoted mechanisms Tg2576 Additionally, robustly suppressed β‐amyloid production accumulation, associated with decreased expression β‐site amyloid precursor protein cleaving 1 (BACE1), possibly through cannabinoid receptor 1‐dependent epigenetic mechanism. These findings improve our understanding AD pathogenesis provide proof concept that selective activity could be promising strategy against AD.