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首页> 外文会议>Meeting on Cell Signaling World: Signal Transduction Pathways as Therapeutic Targets >Altered Subcellular Distribution of the Alzheimer's Amyloid Precursor Protein Under Stress Conditions
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Altered Subcellular Distribution of the Alzheimer's Amyloid Precursor Protein Under Stress Conditions

机译：应激条件下阿尔茨海默氏症淀粉样前体蛋白的亚细胞分布改变

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Altered metabolism of the Alzheimer's amyloid precursor protein (APP) appears to be a key event in the pathogenesis of Alzheimer's disease (AD), and both altered phosphorylation and oxidative stress ap pear to affect the production of the toxic Abeta fragment. Our results show that altered processing of APP was observed under conditions of stress induced by sodium azide in the presence of 2-deoxy-D-glucose (2DG). As previously reported, the production of the secreted fragment of APP (sAPP) was inhibited. Using APP-GFP fusion proteins, we show that 2DG causes the accumulation/delay of APP in the endoplasmic retic ulum (ER)/Golgi (G). The 751 isoform accumulated preferentially in the G, whereas the 695 isoform was blocked preferentially at the ER. This effect was augmented in the presence of sodium azide. APP subcellular distribution was also affected at the plasma membrane. The involve ment of protein phosphorylation in APP subcellular localization was re inforced by the effect of drugs, such as phorbol 12-myristate 13-acetate (PMA), since APP was completely depleted from the membrane in the presence of 2DG and PMA. Thus, the hypothesis that APP is processed in a phosphorylation-dependent manner and that this may be of clin ical relevance appears to hold true even under stress conditions. Our results provide evidence for a role of protein phosphorylation in APP sorting under stress conditions and contribute to the understanding of the molecular basis of AD.
机译：阿尔茨海默氏症淀粉样前体蛋白（APP）的代谢改变似乎是阿尔茨海默氏病（AD）发病机理中的关键事件，并且磷酸化和氧化应激的改变均会影响有毒Abeta片段的产生。我们的结果表明，在2-脱氧-D-葡萄糖（2DG）存在下，在叠氮化钠诱导的应力条件下，APP的加工过程发生了改变。如先前报道的，APP的分泌片段（sAPP）的产生被抑制。使用APP-GFP融合蛋白，我们表明2DG导致内质网（ER）/高尔基体（G）中APP的积累/延迟。 751同工型优先在G中积累，而695同工型则优先在ER处被阻断。在叠氮化钠的存在下，这种作用增强了。 APP亚细胞分布也受到质膜的影响。蛋白质的作用增强了蛋白质磷酸化在APP亚细胞定位中的作用，例如在2DG和PMA的存在下APP完全从膜上耗尽，因此药物的作用是佛波12-肉豆蔻酸13-乙酸酯（PMA）。因此，APP以磷酸化依赖性方式加工且可能具有临床相关性的假设即使在压力条件下也适用。我们的结果提供了蛋白质磷酸化在应激条件下APP排序中的作用的证据，并有助于理解AD的分子基础。

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