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The role of cyclin-dependent kinase 5 in Alzheimer's disease pathogenesis.

机译：细胞周期蛋白依赖性激酶5在阿尔茨海默氏病发病机理中的作用。

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摘要

Cdk5 is a proline-directed serine/threonine protein kinase that regulates the migration of neurons during development of the central nervous system. In Alzheimer's disease brains, the Cdk5 activator p35 is proteolytically cleaved into the truncated p25 form. Generation of p25 disrupts the normal regulation of Cdk5 by causing its prolonged activation and mislocalization. Deregulation of Cdk5 leads to hyperphosphorylation of tau, disruption of the cytoskeleton and neuronal cell death.; Proteolytic cleavage of p35 into p25 is mediated by the calcium-activated cysteine protease calpain. Application of the amyloid β-peptide induces the conversion of p35 to p25 in primary cortical neurons. Inhibition of Cdk5 or calpain activity reduces cell death in Aβ-treated cortical neurons, indicating that the calpain-mediated p35 to p25 conversion pathway is part of the mechanism by which Aβ causes cell death.; One of the downstream targets of Cdk5 is the amyloid precursor protein (APP). APP is phosphorylated on threonine 668 (T668) in the cytoplasmic tail. The p25/Cdk5 kinase induces T668 phosphorylation in primary neurons and in transgenic mice. In the hippocampus of AD brains, T668 phosphorylated APP is upregulated in large pyramidal neurons that, in many cases, also display hyperphosphorylated tau. In these neurons, phosphorylated APP accumulates in large vesicular structures recognized by endosome markers but not by other organelle markers. Cdk5, its activator p25, as well as active m-calpain, all colocalize with phosphorylated APP in these enlarged endosomes. Western blot analysis of brain samples reveals elevated T668 phosphorylated APP C-terminal fragments in many AD hippocampal lysates. Mass spectrometric results further indicate that APP C-terminal fragments are hyperphosphorylated on many other sites, in addition to T668, in AD brain samples. Intriguingly, pharmacological inhibition of Cdk5 activity reduces the production of Aβ peptides in neurons derived from the APP(Sw) transgenic mouse model of Alzheimer's disease. These results suggest that deregulation of Cdk5 and increased phosphorylation of APP in AD brains may have impact on APP processing and Aβ production.
机译：Cdk5是脯氨酸定向的丝氨酸/苏氨酸蛋白激酶，在中枢神经系统发育过程中调节神经元的迁移。在阿尔茨海默氏病大脑中，Cdk5激活剂p35被蛋白水解切割成截短的p25形式。 p25的产生会导致Cdk5的长时间激活和错位，从而破坏Cdk5的正常调控。 Cdk5的失调导致tau的过度磷酸化，细胞骨架的破坏和神经元细胞的死亡。 p35水解为p25的蛋白水解是由钙激活的半胱氨酸蛋白酶钙蛋白酶介导的。淀粉样蛋白β肽的应用可诱导原代皮层神经元中p35转化为p25。抑制Cdk5或钙蛋白酶活性可减少Aβ处理的皮层神经元的细胞死亡，表明钙蛋白酶介导的p35至p25转化途径是Aβ引起细胞死亡的机制的一部分。 Cdk5的下游目标之一是淀粉样前体蛋白（APP）。 APP在细胞质尾巴中的苏氨酸668（T668）上被磷酸化。 p25 / Cdk5激酶在原代神经元和转基因小鼠中诱导T668磷酸化。在AD脑海马中，大型锥体神经元中T668磷酸化的APP被上调，在许多情况下，它们也显示出高磷酸化的tau。在这些神经元中，磷酸化的APP积累在由内体标记物识别但未被其他细胞器标记物识别的大囊泡结构中。在这些扩大的内体中，Cdk5，其激活因子p25以及活性的m-钙蛋白酶都与磷酸化的APP共定位。对脑样本的蛋白质印迹分析显示，在许多AD海马裂解物中，T668磷酸化的APP C末端片段升高。质谱结果进一步表明，在AD脑样本中，除T668之外，APP C末端片段在许多其他位点均被高磷酸化。有趣的是，对Cdk5活性的药理抑制作用可减少源自阿尔茨海默氏病APP（Sw）转基因小鼠模型的神经元中Aβ肽的产生。这些结果表明，AD大脑中Cdk5的失调和APP磷酸化的增强可能对APP加工和Aβ产生有影响。

著录项

  • 作者

    Lee, Ming-Sum.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Biology Neuroscience.; Biology Molecular.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 267 p.
  • 总页数 267
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;分子遗传学;细胞生物学;
  • 关键词

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