Grant: Project Grant

Amyloid plaque is a hallmark of Alzheimer's Disease (AD) neuropathology and the amyloid beta protein (Abeta) is the central component of the plaques. Abeta is derived from APP protein through sequential cleavages by beta-secretase and gamma-secretase. The pathogenic mutations in the presenilin-1 (PS1) gene are the major cause of familial AD (FAD). PS1 is the core component of gamma-secretase to cleave APP and Notch. Notch plays a fundamental role in neurodevelopment. One of the major reasons of the failed AD clinical trials on gamma-secretase inhibitors is that those inhibitors cause abnormalities in gastrointestinal tract, thymus, spleen and skin due to their inhibition of Notch cleavage. We identified a novel FAD-causing PS1 mutation that has differential effects on APP and Notch cleavage. This proposal seeks to investigate how this PS1 mutation selectively regulates APP without affecting Notch cleavage, and to define the mechanism underlying the PS1's role in AD pathogenesis. The study highlights a possibility of developing novel specific gamma-secretase modulators as drugs that inhibit Abeta generation but may maintain normal Notch signaling for AD treatment.