期刊
JOURNAL OF NEUROSCIENCE
卷 33, 期 1, 页码 64-71出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2371-12.2013
关键词
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资金
- Lundbeck Foundation
- Riisforts Foundation
- Lundbeck Foundation [R54-2010-5281] Funding Source: researchfish
The development and progression of Alzheimer's disease is linked to excessive production of toxic amyloid-beta peptide, initiated by beta-secretase cleavage of the amyloid precursor protein (APP). In contrast, soluble APP alpha (sAPP alpha) generated by the alpha-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 alpha-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.
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