Development and Mechanism of γ-Secretase Modulators for Alzheimer's Disease

gamma-Secretase is an aspartyl intramembranal protease composed of presenilin, Nicastrin, Aph1, and Pen2 with 19 transmembrane domains. ?gamma-Secretase cleaves the amyloid precursor proteins (APP) to release A beta peptides that likely play a causative role in the pathogenesis of Alzheimers disease (AD). In addition, gamma-secretase cleaves Notch and other type I membrane proteins. gamma-Secretase inhibitors (GSIs) have been developed and used for clinical studies. However, clinical trials have shown adverse effects of GSIs that are potentially linked with nondiscriminatory inhibition of Notch signaling, overall APP processing, and other substrate cleavages. Therefore, these findings call for the development of disease-modifying agents that target gamma-secretase activity to lower levels of A beta 42 production without blocking the overall processing of gamma-secretase substrates. gamma-Secretase modulators (GSMs) originally derived from nonsteroidal anti-inflammatory drugs (NSAIDs) display such characteristics and are the focus of this review. However, first-generation GSMs have limited potential because of the low potency and undesired neuropharmacokinetic properties. This generation of GSMs has been suggested to interact with the APP substrate, gamma-secretase, or both. To improve the potency and brain availability, second-generation GSMs, including NSAID-derived carboxylic acid and non-NSAID-derived heterocyclic chemotypes, as well as natural product-derived GSMs have been developed. Animal studies of this generation of GSMs have shown encouraging preclinical profiles. Moreover, using potent GSM photoaffinity probes, multiple studies unambiguously have showed that both carboxylic acid and heterocyclic GSMs specifically target presenilin, the catalytic subunit of gamma-secretase. In addition, two types of GSMs have distinct binding sites within the gamma-secretase complex and exhibit different A beta profiles. GSMs induce a conformational change of gamma-secretase to achieve modulation. Various models are proposed and discussed. Despite the progress of GSM research, many outstanding issues remain to be investigated to achieve the ultimate goal of developing GSMs as effective AD therapies.