The retromer complex system in a transgenic mouse model of AD: influence of age
The retromer complex system in a transgenic mouse model of AD: influence of age
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DOI：
10.1016/j.neurobiolaging.2016.12.025
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发表时间：
2017-04-01
影响因子：
4.2
通讯作者：
Pratico, Domenico
中科院分区：
文献类型：
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作者：
Chu, Jin;Pratico, Domenico
在阿尔茨海默病(AD)中已经描述了逆转录复合体介导的逆行运输的缺陷。逆转录酶基因操作调节Tg2576小鼠脑淀粉样变性。然而，该复合体在AD样表型的发育过程中是否发生了变化仍不清楚。本研究检测了3月龄、8月龄和14月龄Tg2576和对照仔猪脑内空泡分类蛋白35(VPS35)、VPS26、VPS29及其货物蛋白、阳离子非依赖性甘露糖6-磷酸受体、山梨素相关受体的表达水平。除VPS29外，大脑皮层中除VPS29外均呈年龄依赖性下降，而小脑中相同蛋白质的水平在任何年龄都没有变化。表达人淀粉样β前体蛋白瑞典突变体的神经细胞也降低了逆转录复合体水平。然而，与药物伴侣的孵育呈剂量依赖性地恢复了这些水平，同时淀粉样β蛋白的减少。我们的研究首次表明，在阿尔茨海默病转基因小鼠模型中，逆转聚体复合体表达水平的变化是年龄和区域依赖的，并且该复合体是一个可行的治疗靶点，因为它的缺陷可以通过逆转聚体伴侣在药物上恢复。(C)2016 Elsevier Inc.保留所有权利。
Deficiencies of the retrograde transport mediated by the retromer complex have been described in Alzheimer's disease (AD). Genetic manipulation of retromer modulates brain amyloidosis in Tg2576 mice. However, whether the complex is altered during the development of the AD-like phenotype remains unknown. In this study we assayed the expression levels of the vacuolar sorting protein 35 (VPS35), VPS26, VPS29, and its cargo proteins, cation independent mannose 6-phosphate receptor, sortilin-related receptor in brains of Tg2576 and controls at the ages of 3, 8, and 14 months. While cortex showed an age-dependent decrease in all but VPS29, levels of the same proteins in the cerebellum were unchanged at any age. Neuronal cells expressing human amyloid beta precursor protein Swedish mutant had also reduced retromer complex levels. However, incubation with a pharmacological chaperone dose-dependently restored these levels together with a reduction in amyloid beta. Our study is the first to show that in a transgenic mouse model of AD the changes in the expression levels of the retromer complex are age and region dependent, and that the complex is a viable therapeutic target since its deficiency can be restored pharmacologically by a retromer chaperone. (C) 2016 Elsevier Inc. All rights reserved.