Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer's disease
Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer's disease
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DOI：
10.1016/j.jprot.2010.12.012
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发表时间：
2011-04-01
影响因子：
3.3
通讯作者：
Breen, Gail A. M.
中科院分区：
文献类型：
--
作者：
Chou, Jose L.;Shenoy, Deepa V.;Breen, Gail A. M.
线粒体结构和功能的改变在阿尔茨海默病（AD）的发病机制中起着重要作用。在本研究中，我们使用定量比较蛋白质组学分析方法来分析AD中线粒体蛋白质组的变化。在这些实验中使用AD的三重转基因小鼠模型（3xTg-AD），其在三种人转基因APP（Swe）、PS1（M146 V）和Tau（P301 L）中具有突变。采用二维差异凝胶电泳（2D-DIGE）和串联质谱法，研究了6个月龄雄性3xTg-AD和非转基因小鼠大脑皮质线粒体蛋白质组的定量差异。我们鉴定了23种不同的蛋白质，其表达水平在三重转基因和非转基因线粒体之间存在显着差异。在转基因AD皮质中观察到下调和上调的线粒体蛋白。在3xTg-AD皮质中失调的蛋白质在多种代谢途径中起作用，包括柠檬酸循环、氧化磷酸化、丙酮酸代谢、糖酵解、氧化应激、脂肪酸氧化、酮体代谢、离子转运、细胞凋亡和线粒体蛋白合成。三重转基因AD小鼠大脑皮质线粒体蛋白质组的这些改变发生在显著的淀粉样斑块和神经元缠结的发展之前，表明线粒体失调是AD的早期事件。(C)2011 Elsevier B. V.保留所有权利。
Mitochondrial structural and functional alterations appear to play to an important role in the pathogenesis of Alzheimer's disease (AD). In the present study, we used a quantitative comparative proteomic profiling approach to analyze changes in the mitochondria] proteome in AD. A triple transgenic mouse model of AD (3xTg-AD) which harbors mutations in three human transgenes, APP(Swe), PS1(M146V) and Tau(P301L), was used in these experiments. Quantitative differences in the mitochondrial proteome between the cerebral cortices of 6-month-old male 3xTg-AD and non-transgenic mice were determined by using two-dimensional difference gel electrophoresis (2D-DIGE) and tandem mass spectrometry. We identified 23 different proteins whose expression levels differed significantly between triple transgenic and non-transgenic mitochondria. Both down-regulated and up-regulated mitochondrial proteins were observed in transgenic AD cortices. Proteins which were dysregulated in 3xTg-AD cortices functioned in a wide variety of metabolic pathways, including the citric acid cycle, oxidative phosphorylation, pyruvate metabolism, glycolysis, oxidative stress, fatty acid oxidation, ketone body metabolism, ion transport, apoptosis, and mitochondrial protein synthesis. These alterations in the mitochondrial proteome of the cerebral cortices of triple transgenic AD mice occurred before the development of significant amyloid plaque and neurofibrillary tangles, indicating that mitochondrial dysregulation is an early event in AD. (C) 2011 Elsevier B.V. All rights reserved.