Ricerc@Sapienza

Despite the progress made in the description and diagnosis, no effective medication to prevent or treat Alzheimer's disease (AD) exists so far; thus novel therapeutic targets for the development of new treatments are urgently needed.
We focus on a heterogeneous family of bioactive lipid signals, the N-acylethanolamides (NAEs), whose endogenous levels can be enhanced by the pharmacological inhibition of their metabolism and whose physiological roles might ensure a multilevel intervention for AD treatment.
The best characterized NAEs are the endocannabinoid anandamide, acting mainly on CB1 receptors, and palmitoylethanolamide and oleoylethanolamide, two potent activators of PPARalpha. Both CB1 and PPARalpha receptors play a key role in several molecular and cellular aspects of neurodegeneration/neuroprotection.
FAAH is the key enzyme metabolizing NAEs in the brain and its expression and activity resulted increased in several neuroinflammatory/neurodegenerative conditions, including AD.
We hypothesize that the pharmacological inhibition of FAAH might provide a novel approach for the development of an effective therapy for AD.
We aim to test our hypothesis in vitro and in vivo, focusing at different molecular, cellular and behavioural levels and addressing the impact of FAAH inhibition on both the early onset and the late progression of AD neuropathology.
To this aim, we will use a triple transgenic model of AD that harbors three mutant human genes (APPswe, PS1M146V, and tauP301L), develops amyloid plaques and neurofibrillary pathology, age-related cognitive decline, impairment in synaptic plasticity and closely mimic the disease progression in humans. In these mice we will evaluate whether the increased tone of endogenous NAEs produced by the chronic treatment with the FAAH inhibitor PF-3845 might have beneficial effects on the neurofunctional alterations and exert potential neuroprotective/neuroregenerative effects.