The endocannabinoid (eCB) system is a lipid signaling system with relevant pro-homeostatic functions, consisting of at least two eCB-binding receptors (type-1 and type-2 cannabinoid receptors), their endogenous ligands (N-arachidonoylethanolamine, AEA, and 2-arachidonoylglycerol, 2-AG), and distinct eCB metabolic enzymes. Recent studies from our group and others indicate that eCB levels and eCB metabolic enzymes change age-dependently in both animal models of Alzheimer¿s disease (AD) and patients diagnosized with mild AD. In addition, stimulation of cannabinoid receptors and inhibition of the major AEA-hydrolyzing enzyme fatty acid amide hydrolase (FAAH) have beneficial effects in AD mice. The overall objective of the present project is to decipher the pivotal role of FAAH in AD pathogenesis, and to provide evidence that FAAH may indeed be a relevant target for improving our knowledge of mechanistic underpinnings of AD pathogenesis. In particular, we aim at providing evidence that FAAH inhibition is beneficial against AD-like pathological changes in mice, and also at disclosing the cellular and molecular mechanisms that underlie the anti-AD effects of FAAH manipulation. Furthermore, we plan to uncover the immunomodulatory effects induced by targeting FAAH in murine microglia, by evaluating whether FAAH inhibition in those immune cells known to be associated with AD pathogenesis may affect their inflammatory responses.
