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

Author:

Andersen Olav M.1,Reiche Juliane1,Schmidt Vanessa1,Gotthardt Michael1,Spoelgen Robert1,Behlke Joachim1,von Arnim Christine A. F.1,Breiderhoff Tilman1,Jansen Pernille1,Wu Xin1,Bales Kelly R.1,Cappai Roberto1,Masters Colin L.1,Gliemann Jørgen1,Mufson Elliott J.1,Hyman Bradley T.1,Paul Steven M.1,Nykjær Anders1,Willnow Thomas E.1

Affiliation:

1. Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany; Massachusetts General Hospital, Charlestown, MA 02129; Lilly Research Laboratories, Indianapolis, IN 46285; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612; Institute of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus, Denmark; and Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia

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.

Publisher

Proceedings of the National Academy of Sciences

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