Development of a High-Throughput Assay for Screening of γ-Secretase Inhibitor with Endogenous Human, Mouse or Drosophila γ-Secretase

Selective lowering of amyloid-β levels with small-molecule γ-secretase inhibitors is a promising therapeutic approach for Alzheimer’s disease. In this work, we developed a high throughput assay for screening of γ-secretase inhibitors with endogenous γ-secretase and a fluorogenic substrate. The IC50 values of known γ-secretase inhibitors generated with this method were comparable with reported values obtained by other methods. The assay was optimized and applied to a small-scale screening of 1,280 compounds. The discovery of several new inhibitors warrants further investigation. This assay was also proven to be easily adopted to test compounds for drosophila and mouse γsecretase, which could be very useful to assess compounds activity against γ-secretase from different species before the in vivo test in animal models.