**8. Conclusion**

γ-Secretase was first identified as a protease that cleaves APP within the transmembrane do‐ main and produces Aβ peptides, which are the main hallmark of AD and are thought to be involved in the pathogenesis in the AD brains. However, the physiological functions of this protease remain to be clarified.

The signaling hypothesis for γ-secretase suggesting that its primary function is to regulate the signaling of type 1 membrane proteins was proposed by analogy of Notch signaling. In the canonical Notch signaling pathway, ligands bind to the extracellular domain of Notch expressed on neighboring cells, and trigger sequential proteolytic cleavage. Finally, NICD is released from the cell membrane by γ-secretase and translocates into the nucleus where it modulates gene expression through binding to transcription factors. Thus, γ-secretase plays a central regulatory role in Notch signaling.

While APP is thought to play central roles in the onset and progression of AD, the physio‐ logical functions of this protein also have not yet been fully elucidated. However, it has been shown that AICD, which is released from the cell membrane by γ-secretase, also translocates to the nucleus and may function as a transcriptional regulator. These observations suggest the existence of a signaling mechanism similar to that of Notch.

In this chapter, we focused on the signaling aspects of APP and its pathological roles in AD. Indeed, we showed that AICD alters gene expression and induces neuron-specific apoptosis. Thus, it is likely that APP has a signaling mechanism similar to that of Notch and that APP signaling is at least partially responsible for the onset and progression of AD. If the APP sig‐ naling hypothesis is correct, several molecules involved in APP signaling may be attractive candidates for the targets of drug discovery for treating AD. Thus, extensive studies about this issue are expected.
