Identification of a novel amyloid precursor protein processing pathway that generates secreted N‐terminal fragments

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The proteolytic processing of the amyloid precursor protein (APP) into the β-amyloid (Aβ) peptide is a central event in AD. While the pathway that generates Aβ is well described, many questions remain concerning general APP metabolism and its metabolites. It is becoming clear that the amino-terminal region of APP can be processed to release small N-terminal fragments (NTFs). The purpose of this study was to investigate the occurrence and generation of APP NTFs in vivo and in cell culture (SH-SY5Y) in order to delineate the cellular pathways implicated in their generation. We were able to detect 17- to 28-kDa APP NTFs in human and mouse brain tissue that are distinct from N-APP fragments previously reported. We show that the 17- to 28-kDa APP NTFs were highly expressed in mice from the age of 2 wk to adulthood. SH-SY5Y studies indicate the generation of APP NTFs involves a novel APP processing pathway, regulated by protein kinase C, but independent of α-secretase or β-secretase 1 (BACE) activity. These results identify a novel, developmentally regulated APP processing pathway that may play an important role in the physiological function of APP.

The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes

“…However, cleavage at position 664 does not appear to require antecedent proteolysis of APP. Besides cleavage by α-, β-, and γ-secretases, several studies have identified other N-terminal fragments (NTFs) of APP in human and rodent tissues that are generated by unknown proteases [28, 102, 136]. …”

“…Besides cleavage of α-, β-, and γ-secretases, several studies have identified additional fragments of sAPP (generated by mechanisms other than α-, β-, or γ-secretase cleavages), which can be detected in human and rodent tissues [28, 102, 136]. In 2009, a lot of excitement was generated by findings from the Tessier-Lavigne lab centering on a sAPP fragment of about 35-kDa that appeared to act as a ligand for death receptor 6 (DR6, also known as TNFRSF21) to control axonal pruning [95].…”

“…Studies using HSV-1-mediated APP expression in the SH-SY5Y neuroblastoma cell line and rat cortical neuronal cultures also discovered an array of APP fragments, some of which were developmentally regulated and modulated by protein kinase C in a secretase-independent manner [28, 136]. It is not known what physiological roles these fragments play or whether they were generated after additional proteolysis of sAPP after secretion.…”

The Role of APP in Structural Spine Plasticity

“…APP can be cleaved by a large number of proteases, which are grouped into α-, β- and γ-secretases, depending on the cleavage site. However, proteases which cleave APP outside these three sites also exist (Vella and Cappai, 2012; Willem et al, 2015; Zhang et al, 2015; Baranger et al, 2016). Depending on the combination of proteases which process APP, a vast number of different cleavage products may be generated, which have various biological properties (Nhan et al, 2015; Andrew et al, 2016).…”

Multiplex Assay for Live-Cell Monitoring of Cellular Fates of Amyloid-β Precursor Protein (APP)

“…Other fragments, such as sAPP-α, sAPP-β and APP intracellular domain (AICD), have paracrine and cell-autonomous regulatory functions, which remain incompletely characterized [8]–[11]. In addition to peptides from the well-characterized α-, β- and γ/ε cleavages, also other cleavage products of APP have been described in specific conditions [12]–[15].…”