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Updated: Aug 19, 2026

Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
Published on: January 25, 2018
Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease
1Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex, UK. Scott_Pollack@merck.com
Abstract:
The proteolytic enzyme gamma-secretase cleaves amyloid precursor protein (beta-APP), following beta-secretase cleavage to generate the amyloid-beta peptides that are causally linked to Alzheimer's disease (AD). However, gamma-secretase is also responsible for intramembranous cleavage of a growing list of additional transmembrane proteins, and therefore therapeutic inhibition of gamma-secretase might also affect these substrates. Such blockade over a chronic period may be deleterious, due to interference with potential cell signaling pathways activated by any of the products of these novel gamma-secretase substrates. In addition, inhibition of gamma-secretase leads to alterations in other beta-APP metabolites, with potential toxicity and signaling implications. The potential consequences of these off-target effects of gamma-secretase inhibitors are reviewed.
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