Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

Olav M. Andersen, Juliane Reiche, Vanessa Schmidt, Michael Gotthardt, Robert Spoelgen, Joachim Behlke, Christine A.F. Von Arnim, Tilman Breiderhoff, Pernille Jansen, Xin Wu, Kelly R. Bales, Roberto Cappai, Colin L. Masters, Jørgen Gliemann, Elliott J. Mufson, Bradley T. Hyman, Steven M. Paul, Anders Nykjsær, Thomas E. Willnow

Research output: Contribution to journalArticle

421 Scopus citations

Abstract

sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid β-peptide (Aβ), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to Aβ, whereas ablation of sorLA expression in knockout mice results in increased levels of Aβ in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into Aβ and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase Aβ production and plaque formation and promote spontaneous AD.

Original languageEnglish
Pages (from-to)13461-13466
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number38
DOIs
StatePublished - Sep 20 2005
Externally publishedYes

Keywords

  • Endocytic receptors
  • Knockout mouse
  • Neurodegeneration
  • Vps10p-domain receptors

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    Andersen, O. M., Reiche, J., Schmidt, V., Gotthardt, M., Spoelgen, R., Behlke, J., Von Arnim, C. A. F., Breiderhoff, T., Jansen, P., Wu, X., Bales, K. R., Cappai, R., Masters, C. L., Gliemann, J., Mufson, E. J., Hyman, B. T., Paul, S. M., Nykjsær, A., & Willnow, T. E. (2005). Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America, 102(38), 13461-13466. https://doi.org/10.1073/pnas.0503689102