**1. Introduction**

accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phos‐ phatidylinositol 3-kinase (PI3K)/Akt-GSK-3beta pathway in Alzheimer mouse mod‐

el. Journal of Biological Chemistry 2011;286(21) 18414-18425.

60 Understanding Alzheimer's Disease

Alzheimer's disease (AD) is an incurable and progressive neurodegenerative disorder and the most common form of dementia that occurs with aging. The main hallmarks of this disease are the extracellular deposition of amyloid plaques and the intracellular aggregation of tangles in the brain [1, 2]. Although the causes of both the onset and progression of AD are still uncertain, much evidence, including results of genetic analysis, indicates that amyloid precursor protein (APP) itself and its proteolytic processing are responsible for AD. Indeed, familial forms of AD (FAD) have mutations [3] or a duplication of the *APP* gene [4] or mutations in the presenilin1 or 2 (*PS1* or *PS2*) genes [5-7] that code for a catalytic component of the γ-secretase complex [8].

Although APP plays a central role in AD [1, 2], the physiological function of this membrane protein is not clear [9]. On the other hand, γ-secretase was first identified as a protease that cleaves APP within the transmembrane domain and produces amyloid-β (Aβ) peptides [10], which are the main constituent of amyloid plaques and are thought to be involved in AD pathogenesis. However, similar to the physiological functions of APP, those of γ-secretase are also still unclear [11, 12].

The signaling hypothesis suggests that the primary function of γ-secretase is to regulate signal‐ ing of type 1 membrane proteins (the amino terminus is extracellular, and the carboxy terminus is cytoplasmic); this was proposed by analogy of Notch signaling [13-15]. Notch is a family of evolutionarily conserved type 1 membrane proteins that mediate the fates of numerous cells in both invertebrates and vertebrates [16-18]. The molecular mechanism of the Notch signaling pathway is unique because it is controlled by proteolytic cleavage reactions [19, 20]. In the can‐ onical Notch signaling pathway, ligands bind to the extracellular domain of Notch expressed

© 2013 Nakayama et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

on neighboring cells and trigger sequential proteolytic cleavage. Finally, the intracellular do‐ main (ICD) of Notch (NICD) is released from the cell membrane by γ-secretase; NICD then translocates into the nucleus where it modulates gene expression through binding to transcrip‐ tion factors. Therefore, γ-secretase plays a central regulatory role in Notch signaling.

Recently, more than five dozen type 1 transmembrane proteins, including Notch and APP, have been reported as substrates for γ-secretase [21]. The ICDs of these proteins are also re‐ leased from the cell membrane [13-15, 22]. Furthermore, it has been shown that some of these ICDs exist in the nucleus. These processes are very similar to those involved in Notch signaling. Thus, the common enzyme γ-secretase modulates the proteolysis and turnover of putative signaling molecules; this suggests that mechanisms similar to the Notch signaling pathway may widely contribute to γ-secretase–regulated signaling [13-15, 23]. Indeed, it has been shown that the ICD of APP (AICD), which is released from the cell membrane by γsecretase, also translocates to the nucleus [24-26] and may function as a transcriptional regu‐ lator [27, 28]. These observations suggest the existence of APP signaling.

To test the hypothesis that APP has a signaling mechanism similar to that of Notch, we es‐ tablished embryonic carcinoma P19 cell lines that overexpressed AICD [29], which may mimic signaling mechanisms. Although neurons differentiated from these cell lines, AICD expression induced dynamic changes in gene expression profile and neuron-specific apopto‐ sis [30]. These results suggest that APP also has a signaling mechanism, which may be close‐ ly related to AD.

In this chapter, we first summarize current research progress regarding Notch, APP, and γsecretase. We also focus on the signaling hypothesis; γ-secretase–regulated mechanisms similar to Notch signaling may widely play roles in signaling events involving type 1 trans‐ membrane proteins, including APP. Next, we review recent evidence supporting the exis‐ tence of APP signaling. Furthermore, we discuss the possibility that APP signaling is involved in the onset and progression of AD.
