γ-secretase as a therapeutic target for the treatment of Alzheimer's disease

An effective, disease-modifying treatment of Alzheimer's disease (AD) remains one of the most significant unmet needs in modern medicine. As a result of the extensive research in the area, the mechanisms underlying the disease are now much better understood than at any time before. A significant amount of evidence points to the central role of beta-amyloid (A beta) peptide-mediated toxicity in the disease etiology and strategies to remove this species from the central nervous system (CNS) have been actively pursued. The enzyme responsible for the final step in A beta synthesis, gamma-secretase, has emerged as an attractive drug target and intensive research has transformed this enzyme from shadowy beginnings into a well characterised member of a new family of intramembrane-cleaving aspartyl proteases. Many inhibitors across diverse structural classes have been discovered and have demonstrated a lowering of central A beta levels in preclinical models of AD. It has also become increasingly evident more recently that gamma-secretase also mediates a range of cleavages of alternative transmembrane peptides most notably the Notch receptor and the functional consequences of this activity have attracted much attention. The ultimate therapeutic benefit of gamma-secretase inhibitors and the effect of alternative, mechanism-based activities can only be judged when clinical data is forthcoming. In this review we describe the literature regarding the discovery of the nature of gamma-secretase, the development of small molecule inhibitors and their in vivo profiles.