TY - JOUR T1 - Sortilin and SorLA Display Distinct Roles in Processing and Trafficking of Amyloid Precursor Protein JF - The Journal of Neuroscience JO - J. Neurosci. SP - 64 LP - 71 DO - 10.1523/JNEUROSCI.2371-12.2013 VL - 33 IS - 1 AU - Camilla Gustafsen AU - Simon Glerup AU - Lone Tjener Pallesen AU - Ditte Olsen AU - Olav M. Andersen AU - Anders Nykjær AU - Peder Madsen AU - Claus Munck Petersen Y1 - 2013/01/02 UR - http://www.jneurosci.org/content/33/1/64.abstract N2 - 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. ER -