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Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
Published on: January 25, 2018
γ-Secretase inhibitors and modulators
Todd E Golde1, Edward H Koo, Kevin M Felsenstein
1Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Biochimica Et Biophysica Acta
|June 25, 2013
Summary
γ-Secretase inhibitors (GSIs) and modulators (GSMs) are investigated for Alzheimer's disease (AD) and cancer. While GSIs show promise, toxicity concerns necessitate careful benefit-risk evaluation for therapeutic use.
Area of Science:
- Biochemistry
- Pharmacology
- Neuroscience
Background:
- γ-Secretase is a key intramembrane protease targeted for various diseases.
- γ-Secretase inhibitors (GSIs) and modulators (GSMs) are under development for Alzheimer's disease (AD) and cancer.
- Non-selective γ-secretase inhibition poses toxicity risks, requiring careful clinical evaluation.
Purpose of the Study:
- To review the development status of GSIs and GSMs.
- To explore biological and pharmacological questions regarding these agents.
- To assess the therapeutic potential and risks of γ-secretase-targeting drugs.
Main Methods:
- Review of preclinical and clinical studies on GSIs and GSMs.
- Analysis of the mechanism of action for both GSIs and GSMs.
- Investigation of γ-secretase substrate interactions beyond amyloid precursor protein (APP).
Main Results:
- GSIs have been tested in human trials for AD and cancer, with potential in other conditions.
- GSMs modulate γ-secretase activity, altering amyloid β (Aβ) peptide profiles.
- Extensive investigation into GSMs' effects on non-APP substrates is lacking.
Conclusions:
- GSIs offer therapeutic potential but require rigorous benefit-risk assessment due to toxicity.
- GSMs present a potentially safer alternative, but their broader substrate effects need further study.
- Continued research into γ-secretase modulators is crucial for developing safer AD therapeutics.
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