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Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA

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Abstract

Proteolytic cleavage of the amyloid precursor protein (APP) by α-, β- and γ-secretases is a determining factor in Alzheimer’s disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aβ production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aβ production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.

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Acknowledgements

We thank Dagmar Gross and Nura Borger for technical assistance. We thank the Advanced Light Microscopy Facility (ALMF) at the European Molecular Biology Laboratory (EMBL) for support. We thank DFG for funding to SK. SK and GH were supported by AFI. SE was supported by funding of the TU (Technical University of Kaiserslautern) Nachwuchsring. We thank Daniel Romero Mujalli for his valuable support on the statistical analyses. We thank Dr. Sheue-Houy Tyan for encouragement to perform this study.

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Author notes

  1. A. C. Gonzalez

    Present address: Institute for Biochemistry, Christian Albrechts University Kiel, 24118, Kiel, Germany

  2. S. M. Schwarz

    Present address: Institute for Medical Virology, University of Frankfurt, 60596, Frankfurt, Germany

  3. Simone Eggert and A. C. Gonzalez are first authors and contributed equally to this work.

Authors and Affiliations

  1. Department of Human Biology and Human Genetics, University of Kaiserslautern, Erwin-Schrödinger-Str. 13, 67663, Kaiserslautern, Germany

    Simone Eggert, A. C. Gonzalez, C. Thomas, S. Schilling, S. M. Schwarz, V. Adam, P. Strecker & Stefan Kins

  2. EMBL, Heidelberg, Germany

    C. Tischer

  3. Institute for Molecular and Cellular Cognition, Center for Molecular University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany

    G. Hermey

  4. Institute for Pathobiochemistry, Molecular Neurodegeneration, University Medical Center of the Johannes Gutenberg-University Mainz, 55099, Mainz, Germany

    C. U. Pietrzik

  5. Department of Neuroscience, University of California San Diego (UCSD), La Jolla, CA, 92093-0662, USA

    E. H. Koo

  6. Max Delbrueck Center for Molecular Medicine, Berlin, Germany

    V. Schmidt & T. E. Willnow

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  1. Simone Eggert
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Eggert, S., Gonzalez, A.C., Thomas, C. et al. Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA. Cell. Mol. Life Sci. 75, 301–322 (2018). https://doi.org/10.1007/s00018-017-2625-7

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