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.
Global population ageing has a dramatic impact over dementia and AD epidemic. However, it would be a tremendous mistake to consider AD as a normal component of ageing. Indeed, AD may be considered an epidemic with an impact not only on patients and their families, but also on the worldwide health care system. The total estimated worldwide cost of dementia is US $818 billion, and it will become a trillion dollar disease by 2018. The impact on economy is linked to the reduction of healthcare costs. The societal impact will consist in potential health and quality of life improvement in the elderly. Today, over 46 million people live with dementia worldwide and this number is expected to increase to 131.5 million by 2050. In December 2013, the UK government took advantage of its presidency of the G8 (now the G7) to launch a Global Action Against Dementia. The outcome was an impressive commitment to identifying a cure or disease-modifying therapy for dementia by 2025.
Developing novel treatments against AD necessitates a high degree of general and mechanistic understanding of its pathogenesis and hopefully we will generate data that will help to expand our knowledge about the mechanisms of AD.We believe that the eCB system is the right subject for intense research activity looking for novel therapeutic targets that may prevent or delay disease progression. Understanding AD onset and progression remains a major challenge for science, thus the scientific impact will be to deep this understanding and spread this knowledge. Indeed, we believe that our project will contribute to unveil many hidden aspects of AD pathophysiology, thus improving mechanistic understanding via the exploration of one of the most promising lipid signaling system, with particular emphasis on the role of its key component FAAH.