The pharmacological inhibition of Fatty acid amide hydrolase ameliorates several aspects of the Alzheimer's-like phenotype in 3xTg-AD mice

Objectives: Acylethanolamides can exert neuroprotective/anti-inflammatory effects in Alzheimer’s disease (AD). The pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH) can increase the endogenous tone of acylethanolamides, such as anandamide. This increase is able to produce selective anxiolytic-like and antidepressant-like effects in rodents. In our project we tested the hypothesis that a chronic treatment with the selective FAAH inhibitor PF-3845 could exert beneficial effects on the onset and/or the progression of the neurofunctional alterations found in the triple transgenic mouse model of AD (3×Tg-AD). 3×Tg-AD mice develop a progressive and age-related neuropathology characterized by amyloid plaques and neurofibrillary tangles deposition, impairment of synaptic plasticity, cognitive decline and a depressive-like behavioural alterations. This complex phenotype starts appearing around 5-6 months of age and is fully expressed during the old age (from 10-12 months) Methods: For this project, both young (“pre-symptomatic” at 4 months of age) and old (“symptomatic” at 10 months of age) male 3×Tg-AD mice were treated with PF-3845 (10 mg/kg) or vehicle (saline, tween80 and PEG, 2 ml/kg) for two months (administered subcutaneously every other day). At the end of the treatments, we tested our hypothesis following an integrated approach, involving behavioural (tests for cognitive and depressive-like alterations), biochemical and immunohistochemical analyses. Results: PF-3845 was able to improve spatial and recognition memory, and to ameliorate the depressive- and anhedonia-like symptoms in both young and old 3×Tg-AD mice. Moreover, PF-3845 reduced beta-amyloid and tau pathology in the hippocampus and frontal cortex of old mice and increased the hippocampal expression of BDNF. Conclusions: PF-3845 treatment was efficacious not only in preventing the onset of the neurofunctional alterations, but also to partially restore these alterations in old symptomatic mice, thus suggesting that FAAH inhibition might represent a promising target for the development of novel anti-Alzheimer’s therapies.