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首页> 外文学位 >Intracellular trafficking of the Alzheimer beta-amyloid precursor protein regulates beta-amyloid peptide generation.
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Intracellular trafficking of the Alzheimer beta-amyloid precursor protein regulates beta-amyloid peptide generation.

机译：Alzheimerβ-淀粉样蛋白前体蛋白的细胞内运输调节β-淀粉样肽的生成。

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摘要

Alzheimer's disease (AD) is a progressive brain disorder that results in the gradual irreversible loss of memory, personality changes and a decline in thinking abilities. These mental losses are directly attributable to the death of neurons and the breakdown of the connections between them caused by two abnormal structures found in the AD brain: amyloid plaques and neurofibrilary tangles. Amyloid plaques are formed from the inappropriate accumulation of pathogenic beta-amyloid (Abeta) peptides, the end products of a series of proteolytic cleavages of the beta-amyloid precursor protein (betaAPP).;Taken together, the results presented in this thesis indicate that betaAPP trafficking and Abeta generation are inextricably intertwined. The hope is that by understanding the regulation of betaAPP trafficking, we will one day soon be able to suggest therapeutically relevant targets for intervention in Abeta generation, which might delay or prevent the onset of this tragic disease.;The doctoral research summarized in this dissertation examines the connection between the intracellular trafficking of betaAPP, and betaAPP's proteolysis to Abeta. The first chapter describes a series of experiments which directly address the great degree of heterogeneity in betaAPP metabolism and Abeta generation. The results presented define the precise intracellular compartments within which varied Abeta peptides are generated, and the compartments from which they are secreted. In addition, we delineate several novel populations of Abeta peptides based upon biochemical parameters such as the optimal pH at which they are generated and their solubility. The following chapter links the generation of Abeta with the intracellular trafficking of betaAPP using one principal assay, the cell-free reconstitution of betaAPP trafficking. This assay allowed us to demonstrate how diverse molecules and drugs can influence the intracellular generation of Abeta, simply by regulating the rate of betaAPP secretion from specific organelles within the secretory pathway. The final chapter extends the results of the previous two chapters, in which the experiments were performed in mammalian cells, to a novel system, the eukaryotic, but unicellular organism, Saccharomyces cerevisiae. The demonstration that budding yeast expressing betaAPP can generated authentic Abeta peptides, suggests that these simple genetically manipulatable cells can provide a system within which the elusive proteolytic enzymes which generate Abeta can be discovered.
机译：阿尔茨海默氏病（AD）是一种进行性脑部疾病，导致逐渐不可逆的记忆力丧失，性格改变和思维能力下降。这些精神损失直接归因于神经元的死亡以及它们之间的联系破裂，这是由AD脑中发现的两种异常结构引起的：淀粉样斑块和神经原纤维缠结。淀粉样蛋白斑块是由致病性β-淀粉样蛋白（Abeta）肽的不适当积累而形成的，β-淀粉样蛋白前体蛋白（betaAPP）的一系列蛋白水解裂解最终产物。 betaAPP贩运与Abeta的产生密不可分。希望是，通过了解betaAPP交易的规律，我们将有一天能够提出与治疗相关的靶点，以干预Abeta的产生，这可能会延迟或预防这种悲剧性疾病的发作。考察了betaAPP的细胞内运输与betaAPP对Abeta的蛋白水解之间的联系。第一章描述了一系列实验，这些实验直接解决了betaAPP代谢和Abeta产生中的高度异质性。给出的结果定义了精确的细胞内区室，在其中生成各种Abeta肽，以及从中分泌它们的区室。此外，我们根据生化参数（如生成它们的最佳pH值及其溶解度）描述了几种新的Abeta肽种群。下一章使用一种主要分析方法将无ββAPP的无细胞重构与Aβ的产生与βAPP的细胞内运输联系起来。该测定法使我们能够证明，通过调节分泌途径中特定细胞器的betaAPP分泌​​速率，各种分子和药物如何影响Abeta的细胞内生成。最后一章将前两章的结果（其中在哺乳动物细胞中进行的实验）扩展到了一个新系统，即真核但单细胞生物酿酒酵母。表达betaAPP的发芽酵母可以产生真实的Abeta肽的论证表明，这些简单的可遗传操作的细胞可以提供一个系统，在其中可以发现产生Abeta的难以捉摸的蛋白水解酶。

著录项

  • 作者

    Greenfield, Jeffrey Peter.;

  • 作者单位

    Weill Medical College of Cornell University.;

  • 授予单位 Weill Medical College of Cornell University.;
  • 学科 Neurosciences.
  • 学位 Ph.D.
  • 年度 1999
  • 页码 182 p.
  • 总页数 182
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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