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.

doi:10.1101/2024.07.23.604774

bioRxiv · 10.1101/2024.07.23.604774

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.

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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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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.. 2024-07-23. FAAH Inhibition as a Path to Mitigate Alzheimer's Disease Progression in Mouse Models of Amyloidosis. https://doi.org/10.1101/2024.07.23.604774

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