Shedding of APP limits its synaptogenic activity and cell adhesion properties

Ronny Stahl,Stefan Kins,Gunter Merdes,Katja Wagner,Sandra Schilling,Simone Eggert,Peter Soba,Tobias Hartmann,Carsten Rupp

doi:10.3389/fncel.2014.00410

Abstract

The amyloid precursor protein (APP) plays a central role in Alzheimer’s disease (AD) and has essential synapse promoting functions. Synaptogenic activity as well as cell adhesion properties of APP presumably depend on trans-cellular dimerization via its extracellular domain. Since neuronal APP is extensively processed by secretases, it raises the question if APP shedding affects its cell adhesion and synaptogenic properties. We show that inhibition of APP shedding using cleavage deficient forms of APP or a dominant negative α-secretase strongly enhanced its cell adhesion and synaptogenic activity suggesting that synapse promoting function of APP is tightly regulated by α-secretase mediated processing, similar to other trans-cellular synaptic adhesion molecules.

Highlights

A new era of Alzheimer’s disease (AD) research began with identification of the Amyloid-β (Aβ) peptide as a major amyloid plaque component (Masters et al, 1985)
We show that inhibition of amyloid precursor protein (APP) shedding using cleavage deficient forms of APP or a dominant negative α-secretase strongly enhanced its cell adhesion and synaptogenic activity suggesting that synapse promoting function of APP is tightly regulated by α-secretase mediated processing, similar to other trans-cellular synaptic adhesion molecules
Cleavage of β-CTF by γ-secretase leads to the secretion of Aβ peptides of various lengths and the release of the APP intracellular domain (AICD) into the cytosol (Weidemann et al, 2002; Kakuda et al, 2006)

Summary

Introduction

A new era of Alzheimer’s disease (AD) research began with identification of the Amyloid-β (Aβ) peptide as a major amyloid plaque component (Masters et al, 1985). APP can first be cleaved in the non-amyloidogenic pathway by α-secretase within the Aβ domain (Esch et al, 1990) In neurons, this cleavage is mainly mediated by the protease ADAM10 (Kuhn et al, 2010; Prox et al, 2013) and releases the APP ectodomain (sAPPα) while generating the membrane-bound C-terminal fragment (α-CTF). This cleavage is mainly mediated by the protease ADAM10 (Kuhn et al, 2010; Prox et al, 2013) and releases the APP ectodomain (sAPPα) while generating the membrane-bound C-terminal fragment (α-CTF) The latter can be further processed again by the γ-secretase complex, resulting in the secretion of a 3-kDa fragment (p3) and the release of AICD (Weidemann et al., 2002)

Methods

Results

Conclusion