Turning the tide on Alzheimer’s disease: Modulation of γ-secretase Review
| Authors: | Luo, J. E.; Li, Y. M. |
| Review Title: | 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. © 2021, The Author(s). |
| Keywords: | inhibitor; mechanism; γ-secretase; modulator; alzheimer’s disease |
| Journal Title: | Cell and Bioscience |
| Volume: | 12 |
| ISSN: | 2045-3701 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2022-01-04 |
| Start Page: | 2 |
| Language: | English |
| DOI: | 10.1186/s13578-021-00738-7 |
| PROVIDER: | scopus |
| PMCID: | PMC8725520 |
| PUBMED: | 34983641 |
| DOI/URL: | |
| Notes: | Review -- Export Date: 1 February 2022 -- Source: Scopus |
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