Mechanism of gamma‐secretase modulators

Amyloid‐beta (Aβ) peptides are believed to be integral to Alzheimer’s disease (AD) pathogenesis through their role in the “amyloid hypothesis,” in which the accumulation of Aβ peptides initiates a cascade of pathological events leading to neurodegeneration and AD. γ‐Secretase is a transmembrane aspartyl protease which cleaves APP to generate Aβ peptides, making γ‐secretase an attractive drug target. However, inhibitors failed in clinical trials due to their unwanted side effects on other γ‐secretase substrates such as Notch. ɣ‐Secretase modulators (GSMs) selectively reduce levels of the pathogenic Aβ species without affecting Notch and overall APP processing. However, many questions on their mechanism still remain. Here we investigate the molecular mechanism of GSMs by (1) investigating the binding site of imidazole GSM E2012 using photoaffinity labeling and molecular docking and (2) investigating combination therapy with different GSMs on reducing Aβ production.