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

Abstract

Although -secretase was first identified as a protease that cleaves amyloid precursor protein (APP) within the transmembrane domain and produces A peptides, which are thought to be pathogenic in Alzheimer's disease (AD), the physiological functions of -secretase have not been fully elucidated. In the canonical Notch signaling pathway, intramembrane cleavage by -secretase serves to release an intracellular domain of Notch that has activity in the nucleus through binding to transcription factors.Recently, it was demonstrated that many type 1 transmembrane proteins, including Notch, Delta, and APP, are substrates for -secretase, and the intracellular domains of these substrates are released from the cell membrane by -secretase. The common enzyme -secretase modulates proteolysis and the turnover of possible signaling molecules has led to the attractive hypothesis that mechanisms similar to Notch signaling contribute widely to proteolysis-regulated signaling pathways. It is likely that APP also has a signaling mechanism, although the physiological functions of APP have not been elucidated.Indeed, we have shown that the intracellular domain of APP (AICD) 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 -secretase-regulated signaling, including APP signaling, which leads to AD.

DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response

“…Previous reports have shown that multiple type I transmembrane proteins, including APP and Notch, exhibit regulatory functions on gene expression after sequential proteolytic processing (37). Specifically, following cleavage by sheddases, namely ␣-secretase, ␤-secretase, or furin, their C-terminal fragments undergo subsequent cleavage by the ␥-secretase to release their intracellular domains (ICDs), which can often translocate into the nucleus to regulate the expression of target genes (38 -40).…”

γ-Secretase — Regulated Signaling and Alzheimer's Disease

“…It has been reported that several other type 1 membrane proteins also follow the RIP mechanism and their ICDs are released from the cell membrane [13,14,22]. For example, as shown in Fig.3, the process of sequential proteolytic cleavage of CD44, which is important for immune system function, is very similar to those of Notch and APP [22].…”

“…The signaling hypothesis suggests that the primary function of γ-secretase is to regulate signaling 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][14][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][17][18].…”

“…The ICDs of these proteins are also released from the cell membrane [13][14][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][14][15]23]. Indeed, it has been shown that the ICD of APP (AICD), which is released from the cell membrane by γ-secretase, also translocates to the nucleus [24][25][26] and may function as a transcriptional regulator [27,28].…”