γ-Secretase-Regulated Mechanisms Similar to Notch Signaling May Play a Role in Signaling Events, Including APP Signaling, Which Leads to Alzheimer’s Disease

Although gamma-secretase was first identified as a protease that cleaves amyloid precursor protein (APP) within the transmembrane domain, thus producing A beta peptides that are thought to be pathogenic in Alzheimer\u27s disease (AD), its physiological functions have not been fully elucidated. In the canonical Notch signaling pathway, intramembrane cleavage by gamma-secretase serves to release an intracellular domain of Notch that shows activity in the nucleus through binding to transcription factors. Many type 1 transmembrane proteins, including Notch, Delta, and APP, have recently been shown to be substrates for gamma-secretase, and their intracellular domains are released from the cell membrane following cleavage by gamma-secretase. The common enzyme gamma-secretase modulates proteolysis and the turnover of possible signaling molecules, which has led to the attractive hypothesis that mechanisms similar to Notch signaling contribute widely to proteolysis-regulated signaling pathways. APP is also likely to have a signaling mechanism, although the physiological functions of APP have not been elucidated. Indeed, we have shown that the intracellular domain of APP alters gene expression and induces neuron-specific apoptosis. These results suggest that APP signaling responds to the onset of AD. Here, we review the possibility of gamma-secretase-regulated signaling, including APP signaling, which leads to AD