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首页> 外文学位 >Studies on the altered protein-tyrosine phosphatase activity in PC12 cells transfected with the human APP(C100) and its significance in neuronal differentiation.
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Studies on the altered protein-tyrosine phosphatase activity in PC12 cells transfected with the human APP(C100) and its significance in neuronal differentiation.

机译：研究人APP（C100）转染的PC12细胞中蛋白质酪氨酸磷酸酶活性的变化及其在神经元分化中的意义。

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摘要

The exact neuropathological mechanism of AD is not fully established, but the progressive accumulation of amyloidogenic beta-peptide (Abeta) deposits in the brain has been well implicated to be one of the major characteristics of AD pathology along with neurofibrillary tangle formation. The pathogenesis of AD might be a multifactorial event and the cause and consequence relationship in neuropathogenesis of AD needs to be established.; In order to understand the molecular basis of cellular proliferation, differentiation, and death, a variety of biochemical, cell biological, and pathological approaches were taken. This study involves the use of PC12 transfectants and transgenic mice overexpressing nontoxic levels of the human APPC100 fragment. The reagents generated from the cellular studies were tested in AD afflicted postmortem human brain tissues.; Biochemical purification of a 33 kd protein, overexpressed in APP C100 transfectants and suggested to be a dimerized product of APP C100, was carried out which separated it from contaminating anti-AnnexinV cross-reactivity. Studies using PC12 transfectants suggested that as a consequence of APPC100 overexpression PC12 cells undergo multiple cellular changes. Two PTPases differentially regulated in APPC100 transfectants compared to control cells, a 130 kd protein related to RPTPalpha and a 50 kd protein related to PTP1B, were identified and partially characterized. The cellular effects of RPTPalpha were studied by DNA transfections and the resultant PC12 transfectants overexpressing RPTPalpha were generated and characterized. RPTPalpha induction resulted in altered NGF responsiveness and the lack of differentiation. Immunocytochemistry with RPTPalpha antibody on AD afflicted human brain tissues showed that RPTPalpha expression was enhanced in a sub-population of neurons, especially some of the tangle-bearing neurons which perhaps are diseased cells.; Data obtained from this research suggests that the expression of exogenous APPC100 somehow alters the normal signal transduction pathways involved in proliferation and differentiation of PC12 cells, either directly or indirectly, by affecting protein tyrosine phosphorylation events dependent on the level of APPC100 produced in the cell. As a consequence of these alterations the cell cannot tolerate abnormal changes and ultimately dies. It is possible that a similar type of cellular event might be happening in the pathogenesis of AD.
机译：AD的确切神经病理学机制尚未完全确立，但是与淀粉样神经原纤维缠结一起形成的淀粉样蛋白形成的β肽（Abeta）沉积物在大脑中的逐渐积累已被认为是AD病理的主要特征之一。 AD的发病机制可能是多因素事件，需要建立AD神经病因果关系。为了了解细胞增殖，分化和死亡的分子基础，采取了多种生化，细胞生物学和病理学方法。这项研究涉及使用PC12转染子和过表达人APPC100片段无毒水平的转基因小鼠。细胞研究产生的试剂已在AD折磨后的人脑组织中进行了测试。进行了33 kd蛋白的生物化学纯化，该蛋白在APP C100转染子中过表达，被认为是APP C100的二聚产物，将其与污染的抗AnnexinV交叉反应性分离。使用PC12转染子的研究表明，由于APPC100过表达，PC12细胞经历了多种细胞变化。与对照细胞相比，APPC100转染子中有两种差异调节的PTP酶，分别是与RPTPalpha相关的130 kd蛋白和与PTP1B相关的50 kd蛋白，并进行了部分鉴定。通过DNA转染研究了RPTPalpha的细胞效应，并生成并表征了过表达RPTPalpha的PC12转染子。 RPTPalpha诱导导致NGF反应性改变和缺乏分化。在患AD的人脑组织上用RPTPalpha抗体进行的免疫细胞化学研究表明，RPTPalpha的表达在神经元的亚群中增强，尤其是一些缠结神经元，可能是患病的细胞。从这项研究获得的数据表明，外源APPC100的表达通过影响蛋白质酪氨酸磷酸化事件而直接或间接改变了参与PC12细胞增殖和分化的正常信号转导途径，这取决于细胞中产生的APPC100的水平。这些改变的结果是细胞不能忍受异常改变并最终死亡。在AD的发病机理中可能会发生类似类型的细胞事件。

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  • 作者

    Kim, Yong.;

  • 作者单位

    University of Rochester.;

  • 授予单位 University of Rochester.;
  • 学科 Biology Molecular.; Biology Neuroscience.; Biology Cell.
  • 学位 Ph.D.
  • 年度 1998
  • 页码 200 p.
  • 总页数 200
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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