γ-Secretase-Regulated Signaling: Notch, APP, and Alzheimer's Disease

γ-Secretase was first identified as a protease that cleaves amyloid precursor protein (APP) and produces Aβ peptides, which are thought to be pathogenic in Alzheimer's disease (AD). However, the physiological functions of this enzyme remain to be clarified. In the canonical Notch signaling pathway, ligands bind to the extracellular domain of Notch and trigger sequential proteolytic cleavage. Finally, the intracellular domain (ICD) of Notch is released from the cell membrane by γ-secretase and translocates to the nucleus where it modulates gene expression through binding to transcription factors. Thus, γ-secretase plays a central regulatory role in the Notch signaling pathway. Recently, it was demonstrated that many type 1 transmembrane proteins, including APP and Notch, are substrates for γ-secretase, and the ICDs of these substrates are released from the cell membrane by γ-secretase. These processes are very similar to those that occur in Notch signaling. Thus, the common enzyme, γ-secretase, modulates proteolysis and the turnover of possible signaling molecules, suggesting that mechanisms similar to Notch signaling may contribute widely to γ-secretaseregulated signaling pathways, including APP signaling which leads to AD. Indeed, we have shown that ICD of APP induces dynamic changes in gene expression and neuron-specific apoptosis. Our findings suggest that APP signaling responds to the onset of AD. Here, we focus on γ-secretase-regulated signaling hypothesis and discuss the possibility that APP signaling may be closely correlated with the onset of AD.