Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA
Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA
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DOI：
10.1007/s00018-017-2625-7
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发表时间：
2018-01-01
影响因子：
8
通讯作者：
Kins, Stefan
中科院分区：
文献类型：
--
作者：
Eggert, Simone;Gonzalez, A. C.;Kins, Stefan
α、β和γ分泌酶对淀粉样蛋白前体蛋白（APP）的蛋白水解裂解是阿尔茨海默病（AD）的决定性因素。这三种酶的活性失衡可导致致病性A β产生的改变。APP的蛋白水解与其亚细胞定位密切相关，因为所涉及的分泌酶分布在不同的细胞室中。APP已被证明以顺式取向二聚化，影响A β的产生。这可能是由APP寡聚状态或APP单体/二聚体定位改变所定义的不同底物性质所解释的。我们在HeLa细胞中使用两种不同的APP二聚化系统来研究后一种假设。二聚化导致APP在高尔基体和质膜上的定位降低，而内质网和内体中的水平升高。此外，我们通过活细胞成像和生化分析观察到APP二聚化影响其与LRP1和SorLA的相互作用，表明APP二聚化调节其与分选分子的相互作用，进而调节其定位和加工。因此，针对APP寡聚化特性的药理学方法可能为治疗AD开辟新的策略。
Proteolytic cleavage of the amyloid precursor protein (APP) by alpha-, beta- and gamma-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic A beta production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting A beta production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.