Activity requires soluble amyloid precursor protein α to promote neurite outgrowth in neural stem cell‐derived neurons via activation of the MAPK pathway

Abstract

It is known that activity modulates neuronal differentiation in the adult brain but the signalling mechanisms underlying this process remain to be identified. We show here that activity requires soluble amyloid precursor protein (sAPP) to enhance neurite outgrowth of young neurons differentiating from neural stem cells. Inhibition of sAPP secretion and anti-APP antibodies both abolished the effect of depolarization on neurite outgrowth, whereas exogenous sAPPalpha, similar to depolarization, induced neurite elongation. Depolarization and sAPPalpha both required active N-methyl-D-aspartic acid receptor (NMDAR) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) recruitment to induce neurite outgrowth. However, depolarization and sAPPalpha played different roles in modulating this signalling cascade. Depolarization induced ERK phosphorylation with fast kinetics via activation of NMDAR. By contrast, acute application of sAPPalpha did not lead to ERK activation. However, continuous generation of sAPPalpha was necessary for depolarization-induced ERK phosphorylation, indicating that sAPPalpha promotes MAPK/ERK recruitment by an indirect mechanism. In addition, we found that blockade of NMDAR down-regulated APP expression, whereas depolarization increased sAPPalpha, suggesting that activity may also act upstream of sAPP signalling by regulating the amount of cellular APP and extracellular sAPPalpha. Finally, we show that soluble amyloid precursor-like protein 2 (sAPLP2), but not sAPLP1, is functionally redundant to sAPP in promoting neurite outgrowth and that soluble members of the APP family require membrane-bound APP to enhance neurite outgrowth. In summary, these experiments indicate a novel role of APP family members in activity-dependent neuronal differentiation.

Functions of the APP gene family in the nervous system: insights from mouse models

“…In particular, there is currently no consensus whether APP/APLPs function primarily as cell surface receptor-like proteins mediating signaling and/or cell adhesion (Soba et al 2005;Anliker and Müller 2006), or whether APP functions are mediated by the secreted ectodomain APPs (Herms et al 2004;Ring et al 2007;Taylor et al 2008). In this regard, although APPsa has been implicated in many physiological processes, including neuroprotection, neurite outgrowth, the modulation of ion channels and synaptic plasticity, and neurogenesis (Mattson et al 1993;Furukawa et al 1996;Mattson and Furukawa 1998;Ring et al 2007;Taylor et al 2008;Perez et al 1997;Gakhar-Koppole et al 2008;Caille et al 2004), the cognate APPsa receptor(s) has not been identified so far. It was therefore met with excitement when a novel N-terminal fragment (N-APP 286 ) derived from APPsb was identified as a ligand for death receptor 6 (DR6), a member of the TNFR gene family (Nikolaev et al 2009).…”

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

“…The proposed biological functions of sAPPα are related to neuritogenesis/ axonal outgrowth, cell proliferation, glial differentiation, and memory and learning-related processes, such as long-term potentiation (LTP), metal homeostasis, and neuroprotection [81,[91][92][93][94][95][96][97]. The detailed physiological role of sAPPα has been extensively reviewed by Chasseigneaux and Allinquant in 2012 [91].…”

The Role of the Anti-Amyloidogenic Secretase ADAM10 in Shedding the APP-like Proteins

“…Recombinant human APLP2 ectodomain expressed in yeast revealed neuritotrophic potential on chick sympathetic neurons similar to that observed with APP [63]. In addition, soluble APLP2 but not APLP1 promoted neurite outgrowth from murine differentiated precursor cells [64]. This observation is in accordance with an accumulation of APLP2 in the mouse olfactory epithelium [65] -a place where continuous turnover of sensory neurons occurs.…”

“…For the APLPs such extracellular ligands besides the heterodimerization with APP have been suggested [84], therefore ligandinduced cleavage with a follow-up signalling might be assumed. A third putative role might be comprised in the shedded ectodomains of the APP-related proteins themselves: as soluble growth factors they can induce neurite outgrowth as has been shown for APLP2 [63,64], probably by binding to membrane-bound APP. Within the scope of an ADAM10-based approach in ADtherapy [90,91,92], however, cleavage of the APP-like proteins APLP1 and 2 in humans has to be considered as thoroughly as for other candidate substrates.…”