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Trafficking in Alzheimer’s Disease: Modulation of APP Transport and Processing by the Transmembrane Proteins LRP1, SorLA, SorCS1c, Sortilin, and Calsyntenin

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Abstract

The amyloid precursor protein (APP), one key player in Alzheimer’s disease (AD), is extensively processed by different proteases. This leads to the generation of diverging fragments including the amyloid β (Aβ) peptide, which accumulates in brains of AD patients. Subcellular trafficking of APP is an important aspect for its proteolytic conversion, since the various secretases which cleave APP are located in different cellular compartments. As a consequence, altered subcellular targeting of APP is thought to directly affect the degree to which Aβ is generated. The mechanisms underlying intracellular APP transport are critical to understand AD pathogenesis and can serve as a target for future pharmacological interventions. In the recent years, a number of APP interacting proteins were identified which are implicated in sorting of APP, thereby influencing APP processing at different angles of the secretory or endocytic pathway. This review provides an update on the proteolytic processing of APP and the interplay of the transmembrane proteins low-density lipoprotein receptor-related protein 1, sortilin-receptor with A-type repeats, SorCS1c, sortilin, and calsyntenin. We discuss the specific interactions with APP, the capacity to modulate the intracellular itinerary and the proteolytic conversion of APP, a possible involvement in the clearance of Aβ, and the implications of these transmembrane proteins in AD and other neurodegenerative diseases.

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Acknowledgments

We thank Prof. Claus Pietrzik for critically reading the manuscript.

Funding

Funding for SE was from the TU Nachwuchsring (University of Kaiserslautern) and SK and GH were supported by Alzheimer Forschung Initiative (AFI).

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Authors and Affiliations

  1. Department of Human Biology and Human Genetics, University of Kaiserslautern, 67663, Kaiserslautern, Germany

    Simone Eggert, Carolin Thomas & Stefan Kins

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

    Guido Hermey

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  1. Simone Eggert
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  2. Carolin Thomas
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  3. Stefan Kins
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  4. Guido Hermey
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Correspondence to Simone Eggert or Guido Hermey.

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Eggert, S., Thomas, C., Kins, S. et al. Trafficking in Alzheimer’s Disease: Modulation of APP Transport and Processing by the Transmembrane Proteins LRP1, SorLA, SorCS1c, Sortilin, and Calsyntenin. Mol Neurobiol 55, 5809–5829 (2018). https://doi.org/10.1007/s12035-017-0806-x

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  • DOI: https://doi.org/10.1007/s12035-017-0806-x

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