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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Proteomic analysis of the brain tissues from a transgenic mouse model of amyloid β oligomers
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Proteomic analysis of the brain tissues from a transgenic mouse model of amyloid β oligomers

机译：淀粉样β寡聚体转基因小鼠模型对脑组织的蛋白质组学分析

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Amyloid β (Aβ) oligomers are presumed to be one of the causes of Alzheimer's disease (AD). Previously, we identified the E693Δ mutation in amyloid precursor protein (APP) in patients with AD who displayed almost no signals of amyloid plaques in amyloid imaging. We generated APP-transgenic mice expressing the E693Δ mutation and found that they possessed abundant Aβ oligomers from 8 months of age but no amyloid plaques even at 24 months of age, indicating that these mice are a good model to study pathological effects of Aβ oligomers. To elucidate whether Aβ oligomers affect proteome levels in the brain, we examined the proteins and phosphoproteins for which levels were altered in 12-month-old APP E693Δ-transgenic mice compared with age-matched non-transgenic littermates. By two-dimensional gel electrophoresis (2DE) followed by staining with SYPRO Ruby and Pro-Q Diamond and subsequent mass spectrometry techniques, we identified 17 proteins and 3 phosphoproteins to be significantly changed in the hippocampus and cerebral cortex of APP E693Δ-transgenic mice. Coactosin like-protein, SH3 domain-bind glutamic acid-rich-like protein 3 and astrocytic phosphoprotein PEA-15 isoform 2 were decreased to levels less than 0.6 times those of non-transgenic littermates, whereas dynamin, profilin-2, vacuolar adenosine triphosphatase and creatine kinase B were increased to levels more than 1.5 times those of non-transgenic littermates. Furthermore, 2DE Western Blotting validated the changed levels of dynamin, dihydropyrimidinase-related protein 2 (Dpysl2), and coactosin in APP E693Δ-transgenic mice. Glyoxalase and isocitrate dehydrogenase were increased to levels more than 1.5 times those of non-transgenic littermates. The identified proteins could be classified into several groups that are involved in regulation of different cellular functions, such as cytoskeletal and their interacting proteins, energy metabolism, synaptic component, and vesicle transport and recycling. These findings indicate that Aβ oligomers altered the levels of some proteins and phosphoproteins in the hippocampus and cerebral cortex, which could illuminate novel therapeutic avenues for the treatment of AD.
机译：淀粉样β（Aβ）低聚物被认为是阿尔茨海默氏病（AD）的原因之一。以前，我们在患有淀粉样蛋白成像的AD患者中发现了几乎没有淀粉样蛋白斑块信号的AD淀粉样蛋白前体蛋白（APP）中的E693Δ突变。我们生成了表达E693Δ突变的APP转基因小鼠，发现它们从8个月大时起就拥有丰富的Aβ寡聚体，但即使在24个月大时也没有淀粉样斑块，这表明这些小鼠是研究Aβ寡聚体病理效应的良好模型。为了阐明Aβ低聚物是否影响大脑中的蛋白质组水平，我们检查了与年龄匹配的非转基因同窝仔相比，在12个月大的APPE693Δ转基因小鼠中蛋白质和磷蛋白水平发生改变的蛋白质和磷蛋白。通过二维凝胶电泳（2DE），然后用SYPRO Ruby和Pro-Q Diamond染色以及随后的质谱技术，我们鉴定出APPE693Δ转基因小鼠的海马和大脑皮层中有17种蛋白质和3种磷蛋白发生了明显变化。辅肌动蛋白样蛋白，SH3结构域结合的富谷氨酸样蛋白3和星形细胞磷酸化蛋白PEA-15同工型2的水平降低到非转基因同窝仔的水平的0.6倍以下，而动力蛋白，profilin-2，液泡腺苷三磷酸酶肌酸激酶B和肌酸激酶B的水平增加到非转基因同窝动物的1.5倍以上。此外，2DE Western Blotting验证了APPE693Δ转基因小鼠中动力蛋白，二氢嘧啶酶相关蛋白2（Dpysl2）和辅肌动蛋白水平的变化。乙二醛酶和异柠檬酸脱氢酶的水平增加到非转基因同窝仔的水平的1.5倍以上。鉴定出的蛋白质可分为几类，参与不同细胞功能的调节，例如细胞骨架及其相互作用的蛋白质，能量代谢，突触成分以及囊泡运输和回收。这些发现表明，Aβ寡聚体改变了海马和大脑皮层中某些蛋白质和磷蛋白的水平，这可能为AD的治疗开辟了新的途径。

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