Notch1 and amyloid precursor protein are competitive substrates for presenilin1-dependent gamma-secretase cleavage

Proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma -secretases results in the production of a highly amyloidogenic A bet a peptide, which deposits in the brains of Alzheimer's disease patients. Si milar gamma -secretase processing occurs in another transmembrane protein, Notch1, releasing a potent signaling molecule, the Notch C-terminal domain. It has been shown that both events are dependent on a presenilin-dependent protease. We now test the hypothesis that activated Notch1 and APP are com petitive substrates for the same proteolytic activity in neurons. Treatment of neurons with the native Notch ligand, Delta, induces endogenous Notch1 intramembraneous cleavage. and diminishes A beta production in a dose-depen dent manner. Complementary experiments showed that the converse was also tr ue. Overexpressing human APP (APP(695SW)) in neurons leads to a decrease in endogenous Notch1 signal transduction, as assessed by a CBF1 luciferase tr anscription assay, by Notch C-terminal domain nuclear translocation in vitr o and by analysis of Notch C-terminal domain generation and Notch1 staining in vivo. In summary, two complementary approaches suggest that APP and Not ch1 are physiologically relevant competitive substrates for gamma -secretas e activity.