Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1

Abstract

Background: β-Amyloid precursor protein (APP) has been reported to play a role in the outgrowth of neurites from cultured neurons. Both cell-surface APP and its soluble, ectodomain cleavage product (APPs-α) have been implicated in regulating the length and branching of neurites in a variety of assays, but the mechanism by which APP performs this function is not understood. Results:Here, we report that APP is required for proper neurite outgrowth in a cell autonomous manner, both in vitro and in vivo. Neurons that lack APP undergo elongation of their longest neurite. Deletion of APLP1 or APLP2, homologues of APP, likewise stimulates neurite lengthening. Intriguingly, wild-type neurons exposed to APPs-α, the principal cleavage product of APP, also undergo neurite elongation. However, APPs-α is unable to stimulate neurite elongation in the absence of cellular APP expression. The outgrowth-enhancing effects of both APPs-α and the deletion of APP are inhibited by blocking antibodies to Integrin β1 (Itgβ1). Moreover, full length APP interacts biochemically with Itgβ1, and APPs-α can interfere with this binding. Conclusion:Our findings indicate that APPs-α regulates the function of APP in neurite outgrowth via the novel mechanism of competing with the binding of APP to Itgβ1.

Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein

“…22) and several proteins have been described to interact with the ectodomain of APP, therefore representing potential APP ligands (23)(24)(25). Besides, secreted soluble APPectodomain fragments have been shown to interact in a ligandlike manner with membrane-bound APP (26,27).…”

“…19,26,34,35), probably acting as a ligand for one or more unknown receptors. In contrast, Nikolaev et al reported recently that the soluble APP N terminus resulting from β-secretase cleavage (APPsβ) acts as ligand for the orphan death receptor six (DR6), leading to axon pruning and neuronal death after deprivation of other trophic factors (36).…”

APLP2 regulates neuronal stem cell differentiation during cortical development

“…Although the role of APP as precursor of amyloid beta in the context of Alzheimer's disease is well understood (Reinhard et al, 2005), the physiological role of APP is still largely unclear. Gain and loss of function studies have suggested a role of APP in neuronal migration (Herms et al, 2004;Young-Pearse et al, 2007), cell-cell adhesion (Soba et al, 2005), neurite outgrowth (Leyssen et al, 2005;Young-Pearse et al, 2008), synapse formation and function (Wang et al, 2009;Weyer et al, 2011), intracellular signalling (Cao and Südhof, 2001;Deyts et al, 2012) see however (Hébert et al, 2006), axonal pruning (Nikolaev et al, 2009) and neurogenesis Ma et al, 2008; for reviews, see Müller et al, 2012;Reinhard et al, 2005). Moreover, observations made in different models are sometimes contradictory and argue at first glance for opposing functions for the APP family.…”

Amyloid precursor protein and neural development

“…Based on these studies, the authors proposed that DCC acts as a modulator and APP as a receptor for netrin 1, in order to maintain proper guidance for commissural axons. However, contrary to these results, another study showed that in utero electroporation of APP shRNA into NPCs lining the lateral ventricle of rat embryos, which were cultured 2 days after electroporation, displayed longer axons than control neurons (Young-Pearse et al, 2008). The above mentioned studies that tackled the role of APP in neurite outgrowth have identified a number of binding partners for APP, including Van Gogh, Abelson tyrosine kinase, netrin 1 and integrin β1, and, interestingly, these proteins were previously linked to cytoskeletal rearrangement.…”