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 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.
Fatty-acid amide hydrolase inhibition mitigates 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.. - In: THE FEBS JOURNAL. - ISSN 1742-4658. - (2025). [10.1111/febs.17403]
Fatty-acid amide hydrolase inhibition mitigates Alzheimer's disease progression in mouse models of amyloidosis
Giacovazzo G.;Tortolani D.;Businaro R.;Armeli F.;Coccurello R.;
2025
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 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 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
