The selective inhibition of FAAH ameliorates cognitive decline, depressive-like symptoms and neuropathological alterations in a murine model of Alzheimer's disease

Background and Aim: The endocannabinoid system is involved in a wide range of physiological processes, including memory and cognition (1). Overwhelming evidence showed the neuroprotective effects associated to the increased tone of acylethanolamides, which could be used as a novel therapeutic strategy for Alzheimer’s disease (AD). The pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH) is able to increase the endogenous tone of anandamide and other acylethanolamides, leading to cognitive improvements and to anxiolytic- and antidepressant-like effects in rodents. Nevertheless, the phase I clinical trial with BIA 10–2474, a non-selective FAAH inhibitor, has been discontinued due to severe adverse effects caused by the treatment (2). Therefore, in our project we tested the hypothesis that a chronic treatment with the highly selective FAAH inhibitor PF-3845 could exert beneficial effects on the onset and/or the progression of the AD. We used in this study a triple transgenic mouse model of AD (3×Tg-AD), which develop a progressive and age-related neuropathology (cognitive decline, depressive-like symptoms, amyloid β (Aβ) and tau pathology) around 5-6 months of age and is fully expressed during the old age (10 to 12 months). Methods: Both young (presymptomatic) and old (symptomatic) male 3×Tg-AD mice were treated every other day with PF-3845 (10 mg/kg, s.c.) or vehicle (2 ml/kg, s.c.) for two months. At the end of the treatments, we evaluated the effect of the pharmacological treatment by using an integrated approach involving behavioural (tests for cognitive and depressive-like alterations), biochemical and immunohistochemical analyses (evaluation of Aβ, tau and brain-derived neurotrophic factor (BDNF)), as well as neurochemical analyses of the central monaminergic system by HPLC. Results: PF-3845 was able to improve spatial and recognition memory, and to ameliorate the depressive-like symptoms in both young and old 3×Tg-AD mice (n=10). Moreover, PF-3845 treatment reduced Aβ and tau pathology in the frontal cortex and hippocampus (n=4), increased the hippocampal expression of BDNF (n=3) and modulated the monoamine levels in both brain regions (n=4/6). Conclusion: PF-3845 was efficacious in preventing the onset of the AD-like neuropathology and to partially restore the brain alterations in old mice, suggesting that the selective FAAH inhibition may represent a promising target for the development of novel and efficacious therapies for AD.