Copper Promotes the Trafficking of the Amyloid Precursor Protein
Copper Promotes the Trafficking of the Amyloid Precursor Protein
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DOI：
10.1074/jbc.m110.128512
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发表时间：
2011-03-11
影响因子：
4.8
通讯作者：
Camakaris, James
中科院分区：
文献类型：
--
作者：
Acevedo, Karla M.;Hung, Ya Hui;Camakaris, James
淀粉样β肽在大脑皮层和海马区的积累是阿尔茨海默病的主要病理特征。淀粉样β肽由淀粉样前体蛋白（APP）的连续蛋白酶切割产生。我们以前报道过，铜增加APP在细胞表面的水平。在这里，我们报告说，铜，而不是铁或锌，促进APP贩运培养极化上皮细胞和神经元细胞。在SH-SY 5 Y神经元细胞和原代皮层神经元中，铜促进APP从核周定位到更广泛的分布，包括神经突的再分布。重要的是，APP定位的变化并不归因于APP蛋白合成的上调。使用活细胞成像和内吞测定，我们发现铜促进细胞表面APP增加，增加其胞吐作用和减少其内吞作用，分别。本研究确定了一种新的机制，铜调节APP的定位和可能的功能，这对于理解APP在铜稳态中的作用以及铜在阿尔茨海默病中的作用具有重要意义。
Accumulation of the amyloid beta peptide in the cortical and hippocampal regions of the brain is a major pathological feature of Alzheimer disease. Amyloid beta peptide is generated from the sequential protease cleavage of the amyloid precursor protein (APP). We reported previously that copper increases the level of APP at the cell surface. Here we report that copper, but not iron or zinc, promotes APP trafficking in cultured polarized epithelial cells and neuronal cells. In SH-SY5Y neuronal cells and primary cortical neurons, copper promoted a redistribution of APP from a perinuclear localization to a wider distribution, including neurites. Importantly, a change in APP localization was not attributed to an up-regulation of APP protein synthesis. Using live cell imaging and endocytosis assays, we found that copper promotes an increase in cell surface APP by increasing its exocytosis and reducing its endocytosis, respectively. This study identifies a novel mechanism by which copper regulates the localization and presumably the function of APP, which is of major significance for understanding the role of APP in copper homeostasis and the role of copper in Alzheimer disease.