Turning the tide on Alzheimer's disease: modulation of γ-secretase

Abstract

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.

Keywords: Alzheimer’s disease; Inhibitor; Mechanism; Modulator; γ-secretase.

Fig. 1

γ-secretase and its obligatory subunits. Catalytic aspartyl residues are indicated by stars. Adapted from “Gamma secretase” by BioRender.com (2021)

Fig. 2

APP processing by γ-secretase. β-secretase cleaves APP to generate βCTF (C99) and release soluble APP (sAPPβ). Afterwards γ-secretase cleaves βCTF between Aβ49 or Aβ48 (ε-cleavage), resulting in two product lines. Further processing (ζ- and γ- cleavages) generates Aβ peptides released into the extracellular space. Created with BioRender.com

Fig. 3

Structures of γ-secretase inhibitors in AD clinical trials

Fig. 4

Structures of representative first generation γ-secretase modulators

Fig. 5

Structures of representative second generation γ-secretase modulators (A) Carboxylic acid NSAID-derived GSMs and (B) Heterocyclic non-NSAID derived GSMs

Fig. 6

Structures of γ-secretase modulators in clinical trials

Fig. 7

Multiple binding sites on PS1 established by photoaffinity labeling studies. L458 binds to the active site. GSMs such as GSM-1 and E2012 bind to allosteric sites and alter the conformation of the active site

Fig. 8

Visualization of γ-secretase bound to Semagacestat, Avagacestat, and L-685,458. PS1 is represented in orange. Protein Data Bank entries 6LR4, 6LQG, and 7C9I, respectively

Fig. 9

A Visualization of γ-secretase bound to E2012. PS1 is represented in orange and NCT is represented in green. Hydrogen bond between methylimidazole on E2012 and Tyr106 on PS1 is indicated by the dotted blue line. B Visualization of allosteric site and active site on γ-secretase. γ-secretase subunits represented are PS1 (green), Nicastrin (blue), PEN-2 (pink), and APH-1 (brown). Protein Data Bank entry 7D8X