title: Sortilin and SorLA display distinct roles in processing and trafficking of amyloid precursor protein.
abstract: The development and progression of Alzheimer's disease is linked to excessive production of toxic amyloid-β peptide, initiated by β-secretase cleavage of the amyloid precursor protein (APP). In contrast, soluble APPα (sAPPα) generated by the α-secretase is known to stimulate dendritic branching and enhance synaptic function. Regulation of APP processing, and the shift from neurotrophic to neurotoxic APP metabolism remains poorly understood, but the cellular localization of APP and its interaction with various receptors is considered important. We here identify sortilin as a novel APP interaction partner. Like the related APP receptor SorLA, sortilin is highly expressed in the CNS, but whereas SorLA mainly colocalizes with APP in the soma, sortilin interacts with APP in neurites. The presence of sortilin promotes α-secretase cleavage of APP, unlike SorLA, which inhibits the generation of all soluble products. Also, sortilin and SorLA both bind and mediate internalization of sAPP but to different cellular compartments. The interaction involves the 6A domain of APP, present in both neuronal and non-neuronal APP isoforms. This is important as sAPP receptors described so far only bind the non-neuronal isoforms, leaving SorLA and sortilin as the only receptors for sAPP generated by neurons. Together, our findings establish sortilin, as a novel APP interaction partner that influences both production and cellular uptake of sAPP.
authors.affiliation: The Lundbeck Foundation Research Centre MIND, Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark. cg@biokemi.au.dk
authors.forename: Camilla
authors.initials: C
authors.lastname: Gustafsen
authors.forename: Simon
authors.initials: S
authors.lastname: Glerup
authors.forename: Lone Tjener
authors.initials: LT
authors.lastname: Pallesen
authors.forename: Ditte
authors.initials: D
authors.lastname: Olsen
authors.forename: Olav M
authors.initials: OM
authors.lastname: Andersen
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjær
authors.forename: Peder
authors.initials: P
authors.lastname: Madsen
authors.forename: Claus Munck
authors.initials: CM
authors.lastname: Petersen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D000099183:Sortilin; C102582:SORL1 protein, human