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Clathrin adaptor AP-1–mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2022-06-23 , DOI: 10.1016/j.jbc.2022.102172
Yunan C Januário 1 , Jessica Eden 2 , Luan S de Oliveira 3 , Raffaella De Pace 4 , Lucas A Tavares 1 , Mara E da Silva-Januário 1 , Vinícius B Apolloni 1 , Elise L Wilby 2 , Randolf Altmeyer 5 , Patricia V Burgos 6 , Sonia A L Corrêa 7 , David C Gershlick 2 , Luis L P daSilva 1
Affiliation  

One of the hallmarks of Alzheimer’s disease is the accumulation of toxic amyloid-β (Aβ) peptides in extracellular plaques. The direct precursor of Aβ is the carboxyl-terminal fragment β (or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in Alzheimer’s disease brains, and its intracellular accumulation has been linked to early neurotoxicity independently of Aβ. Despite this, the causes of increased C99 levels are poorly understood. Here, we demonstrate that APP interacts with the clathrin vesicle adaptor AP-1 (adaptor protein 1), and we map the interaction sites on both proteins. Using quantitative kinetic trafficking assays, established cell lines and primary neurons, we also show that this interaction is required for the transport of APP from the trans-Golgi network to endosomes. In addition, disrupting AP-1-mediated transport of APP alters APP processing and degradation, ultimately leading to increased C99 production and Aβ release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.



中文翻译:


网格蛋白接头 AP-1 介导的高尔基体淀粉样前体蛋白的输出对于神经毒性淀粉样蛋白片段的产生至关重要



阿尔茨海默氏病的标志之一是有毒的β淀粉样蛋白(Aβ)肽在细胞外斑块中积累。 Aβ 的直接前体是淀粉样前体蛋白 (APP) 的羧基末端片段 β(或 C99)。在阿尔茨海默病大脑中检测到的 C99 水平升高,其细胞内积累与早期神经毒性有关,与 Aβ 无关。尽管如此,C99 水平升高的原因仍知之甚少。在这里,我们证明 APP 与网格蛋白囊泡接头 AP-1(接头蛋白 1)相互作用,并绘制了两种蛋白上的相互作用位点。使用定量动力学运输测定、建立的细胞系和原代神经元,我们还表明这种相互作用是 APP 从反式高尔基体网络运输到内体所必需的。此外,破坏 AP-1 介导的 APP 运输会改变 APP 的加工和降解,最终导致 C99 产量和 Aβ 释放增加。我们的结果表明 AP-1 调节 APP 的亚细胞分布,改变其加工成神经毒性片段的过程。

更新日期:2022-06-23
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