γ-secretase is a membrane-embedded aspartyl protease carrying out cleavage of more than 100 single transmembrane-spanning proteins, including APP, Notch, N-cadherin, etc. Its subunit, presenilin (PS) is the catalytic component, of which mutations are a major cause of early onset familial Alzheimer disease (FAD). These mutations lead to an increase in the production of the highly amyloidogenic Aβ42 isoform. Drugs aimed at γ-secretase are now considered to be promising therapeutic targets for AD. γ-secretase inhibitors (GSIs) were first introduced into clinical trials due to their efficacy in lowering Aβ production, but later were found to cause severe adverse events due to their blockage of the Notch signaling process. γ-secretase modulators (GSMs) were developed to modulate γ-secretase activity by selectively targeting Aβ42 reduction over the Notch pathway, which have been shown to have less side effects. Although clinical studies show that none of the GSIs or GSMs have been proven to be fully effective, they shed light on the physiological role of γ-secretase and PS in AD development. At the same time, natural products, due to their structural diversity and pleiotropic profile, can modulate γ-secretase activity in a dose-dependent manner, broadening our vision of drug development. With the structural information of γ-secretase released recently, we speculate there will be an explosion of γ-secretase modulators targeting not only the proteolysic center but also the interaction of its different components.
Keywords: Alzheimer disease, γ-secretase inhibitors, γ-secretase modulators, Natural products, Presenilin.