Shedding of APP limits its synaptogenic activity and cell adhesion properties

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

doi:10.3389/fncel.2014.00410

Shedding of APP limits its synaptogenic activity and cell adhesion properties

Front Cell Neurosci. 2014 Dec 3:8:410. doi: 10.3389/fncel.2014.00410. eCollection 2014.

Authors

Ronny Stahl¹, Sandra Schilling², Peter Soba³, Carsten Rupp², Tobias Hartmann⁴, Katja Wagner⁵, Gunter Merdes⁶, Simone Eggert², Stefan Kins⁷

Affiliations

¹ Center of Molecular Biology ZMBH, University of Heidelberg Heidelberg, Germany ; Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich Munich, Germany.
² Department of Human Biology and Human Genetics, Technical University of Kaiserslautern Kaiserslautern, Germany.
³ Center of Molecular Biology ZMBH, University of Heidelberg Heidelberg, Germany ; Center for Molecular Neurobiology (ZMNH), University of Hamburg Hamburg, Germany.
⁴ Deutsches Institut für DemenzPrävention, Experimental Neurology, Saarland University Homburg/Saar, Germany.
⁵ Center of Molecular Biology ZMBH, University of Heidelberg Heidelberg, Germany ; Department of Human Biology and Human Genetics, Technical University of Kaiserslautern Kaiserslautern, Germany.
⁶ Center of Molecular Biology ZMBH, University of Heidelberg Heidelberg, Germany ; Department of Biosystems Science and Engineering, ETH Zürich Basel, Switzerland.
⁷ Center of Molecular Biology ZMBH, University of Heidelberg Heidelberg, Germany ; Department of Human Biology and Human Genetics, Technical University of Kaiserslautern Kaiserslautern, Germany ; Deutsches Institut für DemenzPrävention, Experimental Neurology, Saarland University Homburg/Saar, Germany.

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.

Keywords: APP processing; Alzheimer’s disease; SAM; amyloid precursor protein; cell adhesion; synaptogenic activity.