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[iTRAQ] 阿尔茨海默病-iTRAQ

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发表于 2015-12-28 16:09:16 | 显示全部楼层 |阅读模式

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Proc Natl Acad Sci U S A.2009 Nov 24;106(47):20057-62. doi: 10.1073/pnas.0905529106. Epub 2009 Nov 6.
Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer'sdisease mice.
IF=
14年9.674
13年9.809
12年9.737
11年9.681
研究关键词:阿尔茨海默病,iTRAQ,小鼠,线粒体
研究概要:
    阿尔茨海默病(AD)的特点是β淀粉样蛋白斑形成、神经纤维交联、神经元和突触消失。既往的研究证实tau突变的PR5转基因小鼠会发生神经纤维交联,而APP/PS2双转基因小鼠会发生β淀粉样但白斑形成,本研究以杂交品系PR5/APP/PS2小鼠、APP/PS2小鼠、PR5小鼠及野生型小鼠为研究对象,分别在8周、12周时采样,用iTRAQ技术检测4组样本的差异蛋白,研究发现差异蛋白多为氧化磷酸化系统的复合体IIV相关的蛋白,其中复合体I相关蛋白的表达改变为tau依赖性,复合体IV相关蛋白的表达改变为Aβ依赖性,值得注意的是,本研究数据证实了tauAβ的功能具有协同作用。本研究为AD的机制的进一步研究提供了重要的实验依据。
Abstract
Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta)-containing plaques, neurofibrillary tangles, and neuron and synapse loss. Tangle formation has been reproduced in P301L tau transgenic pR5 mice, whereas APP(sw)PS2(N141I) double-transgenic APP152 mice develop Abeta plaques. Cross-breeding generates triple transgenic ((triple)AD) mice that combine both pathologies in one model. To determine functional consequences of the combined Abeta and tau pathologies, we performed a proteomic analysis followed by functional validation. Specifically, we obtained vesicular preparations from (triple)AD mice, the parental strains, and nontransgenic mice, followed by the quantitative mass-tag labeling proteomic technique iTRAQ and mass spectrometry. Within 1,275 quantified proteins, we found a massive deregulation of 24 proteins, of which one-third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Notably, deregulation of complex I was tau dependent, whereas deregulation of complex IV was Abeta dependent, both at the protein and activity levels. Synergistic effects of Abeta and tau were evident in 8-month-old (triple)AD mice as only they showed a reduction of the mitochondrial membrane potential at this early age. At the age of 12 months, the strongest defects on OXPHOS, synthesis of ATP, and reactive oxygen species were exhibited in the (triple)AD mice, again emphasizing synergistic, age-associated effects of Abeta and tau in perishing mitochondria. Our study establishes a molecular link between Abeta and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.
PMID: 19897719
免费全文链接:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774257/

PNAS-2009-IF9.809-转基因小鼠模型.pdf

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