URB-597

Oddi et al. report the effects of chronic treatment via intranasal delivery with URB597, a fatty acid amide hydrolase (FAAH) inhibitor, on an Alzheimer's disease (AD) transgenic mouse model. They found that prolonged treatment with URB597 reduced the learning and memory deficits of these mice. Mechanistically, the inhibitor modified several genes related to amyloidosis and inflammatory responses or anandamide signaling. FAAH inhibition induced a decrease in the accumulation, synthesis, and release of β‐Amyloid, along with diminished expression of β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1), and this change may be associated with epigenetic changes induced by the drug. In summary, prolonged treatment with URB597 impinges on different aspects of AD pathophysiology, suggesting its therapeutic relevance in treating AD.

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.