FAAH INHIBITION ATTENUATES SEX-DEPENDENT NEUROINFLAMMATORY RESPONSES IN THE 5XFAD MODEL OF ALZHEIMER'S DISEASE

The endocannabinoid system (ECS) represents a promising therapeutic target for neurodegenerative diseases due to its role in neuronal homeostasis and inflammation regulation. Fatty acid amide hydrolase (FAAH), responsible for anandamide degradation, is a key modulator of glial activity and neuroinflammation and has therefore emerged as an attractive pharmacological target in the context of neurodegenerative disorders.
We evaluated the effects of chronic FAAH inhibition on neuroinflammatory responses in the 5xFAD mouse model of Alzheimer's disease, with emphasis on sex-dependent mechanisms. Six-month-old male and female 5xFAD mice received the irreversible FAAH inhibitor PF-04457845 orally (10 mg/kg) for three months. Behavioral assessments evaluated spatial memory, anxiety, and depression-like behaviors. Molecular and cellular analyses characterized microglial and astrocytic reactivity via flow cytometry and qPCR; inflammasome components, microglial signaling pathways, glial activation markers, and synaptic integrity were analyzed by Western blot and immunohistochemistry.
Vehicle-treated females exhibited significantly higher microglial activation and an exacerbated inflammatory profile compared to males. FAAH inhibition attenuated these inflammatory processes in females, reducing pro-inflammatory mediators and glial reactivity while preserving synaptic stability. Males displayed more modest treatment effects, revealing sex-specific ECS regulation in neuroinflammatory control.
These findings highlight significant sexual dimorphism in neuroinflammatory mechanisms and support FAAH as a promising therapeutic target in AD, suggesting that sex-specific therapeutic strategies merit further investigation.
PID2022-138461OB-I00, supported by MICIU/AEI /10.13039/501100011033 and by FEDER, UE.