title: Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
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 beta-peptide (Abeta), 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 Abeta, whereas ablation of sorLA expression in knockout mice results in increased levels of Abeta in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into Abeta and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase Abeta production and plaque formation and promote spontaneous AD.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany.
authors.forename: Olav M
authors.initials: OM
authors.lastname: Andersen
authors.forename: Juliane
authors.initials: J
authors.lastname: Reiche
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schmidt
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Robert
authors.initials: R
authors.lastname: Spoelgen
authors.forename: Joachim
authors.initials: J
authors.lastname: Behlke
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
authors.forename: Tilman
authors.initials: T
authors.lastname: Breiderhoff
authors.forename: Pernille
authors.initials: P
authors.lastname: Jansen
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Jørgen
authors.initials: J
authors.lastname: Gliemann
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D011992:Endosomes / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058225:Plaque, Amyloid / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; C102582:SORL1 protein, human