Alzheimer's disease (AD) is the most common type of
neurodegenerative disorder.
Amyloid-beta (Aβ) plaques are integral to the "
amyloid hypothesis," which states that the accumulation of Aβ
peptides triggers a cascade of pathological events leading to neurodegeneration and ultimately AD. While the FDA approved
aducanumab, the first Aβ-targeted
therapy, multiple safe and effective treatments will be needed to target the complex pathologies of AD. γ-
Secretase is an intramembrane
aspartyl protease that is critical for the generation of Aβ
peptides. Activity and specificity of γ-
secretase are regulated by both obligatory subunits and modulatory
proteins. Due to its complex structure and function and early clinical failures with pan inhibitors, γ-
secretase has been a challenging
drug target for AD. γ-
secretase modulators, however, have dramatically shifted the approach to targeting γ-
secretase. Here we review γ-
secretase and small molecule modulators, from the initial characterization of a subset of
NSAIDs to the most recent clinical candidates. We also discuss the chemical biology of γ-
secretase, in which small molecule probes enabled structural and functional insights into γ-
secretase before the emergence of high-resolution structural studies. Finally, we discuss the recent crystal structures of γ-
secretase, which have provided valuable perspectives on substrate recognition and molecular mechanisms of small molecules. We conclude that modulation of γ-
secretase will be part of a new wave of AD
therapeutics.