CELL-BASED SMALL-MOLECULE SCREENING IDENTIFIES A Γ-SECRETASE MODULATOR INVOLVED IN APP PROCESSING

The accumulation of amyloid-beta (Aβ) plaques in the brain is one of the hallmarks of Alzheimer’s disease (AD) pathology. Aβ is generated through the proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretase. Despite numerous attempts to regulate Aβ production through γ-secretase inhibition, most clinical trials have been unsuccessful due to severe side effects, primarily caused by the inhibition of Notch, a key γ-secretase substrate. Therefore, selectively modulating γ-secretase activity has emerged as a promising therapeutic strategy for treating AD.
In this study, we developed a cell-based reporter system to monitor γ-secretase-mediated APP cleavage activity. Using this system, we screened a library of 2,570 FDA-approved drugs and identified several compounds with potential γ-secretase modulating effects. We administered candidate compounds to AD mouse models, followed by variousbehavioral tests to evaluate cognitive function. Additionally, histochemical and biochemical analyses were conducted to verify the modulation of γ-secretase activity.
One candidate, referred to as Compound A (Cpd A), significantly improved cognitive performance in 5xFAD mouse models. Further analyses revealed that Cpd A treatment reduced Aβ42 levels and Aβ plaque burden in the brains of the AD mice. Transcriptomic analysis identified significant changes in gene expression following Cpd A administration. In neuronal cells, the treatment of Cpd A reduced the interaction between γ-secretase and APP, leading to a decrease in APP cleavage.
Our findings demonstrate the therapeutic potential of Compound A as a selective γ-secretase modulator and provide insights into the roles of γ-secretase in Alzheimer’s disease pathology.