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Uncovering a new model of intracellular processing of the amyloid precursor protein: Towards a test of the amyloid hypothesis.

机译：发现淀粉样前体蛋白的细胞内加工的新模型：对淀粉样假说的检验。

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The deposition of amyloid-beta peptides (Abeta) in senile plaques (SPs) is a central pathological feature of Alzheimer's disease (AD). Abeta is produced by proteolytic cleavage of the amyloid precursor protein (APP) by activities termed beta- and gamma-secretase. The goals of this dissertation are to develop insights into the intracellular pathways that lead to the production of Abeta from APP. The studies described here are driven by the hypothesis that perturbations in APP processing that increase Abeta production promote the accumulation of SPs in the AD brain and that SPs initiate an inflammatory and neurotoxic cascade leading to neuronal death. Testing of this hypothesis requires identification of the intracellular processing pathways for Abeta production, determination of the regulation of these pathways, understanding of the mechanisms that underlie plaque formation, and methods to inhibit and monitor plaque formation in vivo. Towards these ends, this dissertation provides evidence that Abeta1-42, the major constituent of SPs, is produced in the endoplasmic reticulum and accumulates over time in an insoluble form that may serve as a nidus for plaque generation. Moreover, we found that the exclusive production of Abeta1-42 in the endoplasmic reticulum results from the expression of a distinct gamma-secretase in this organelle. We demonstrate that this gamma-secretase competes with the proteasome for cleavage of APP carboxyl-terminal fragments. In addition, we examined the mechanism by which protein kinase-C (PKC) activation increases the non-amyloidogenic alpha-secretase cleavage of APP. We found that PKC activation increases alpha-secretase cleavage not by changing APP trafficking but rather by activating specific metalloproteases responsible for alpha-secretase activity. Significantly, these proteases are localized in the trans-Golgi network, another known site of Abeta generation. This colocalization results in competition between non-amyloidogenic (alpha-secretase) and amyloidogenic (beta-secretase) processing of APP. Finally, we generated an amyloid-binding probe (BSB) and showed that it is specific and sensitive for SPs and that it crosses the blood-brain barrier. BSB detected SPs in a mouse model of amyloidogenesis and may therefore be useful for the diagnosis and evaluation of AD patients. The preceding studies further our understanding of intracellular processing of APP, and provide data useful for the generation of specific inhibitors of Abeta production. The combined use of inhibitors of Abeta production with radiological monitoring of plaque deposition in AD patients will allow testing of the links between Abeta production, plaque burden, and clinical dementia.
机译：淀粉样蛋白β肽（Abeta）在老年斑（SPs）中的沉积是阿尔茨海默病（AD）的主要病理特征。 Abeta是由淀粉样前体蛋白（APP）通过称为β-和γ-分泌酶的活性进行蛋白水解切割而产生的。本文的目的是对导致APP产生Abeta的细胞内途径进行深入研究。此处描述的研究受到以下假设的推动：APP处理过程中的扰动会增加Abeta的产生，从而促进SP在AD脑中的蓄积，而SP会引发炎症和神经毒性级联反应，从而导致神经元死亡。要对该假设进行检验，需要鉴定出产生Abeta的细胞内加工途径，确定这些途径的调节，了解噬菌斑形成的基础机制以及在体内抑制和监测噬菌斑形成的方法。为此，本论文提供了证据，证明SP的主要成分Abeta1-42在内质网中产生，并随着时间的推移以不溶形式积聚，可作为噬菌斑的产生菌。此外，我们发现内质网中Abeta1-42的独家生产是由于该细胞器中独特的γ-分泌酶的表达所致。我们证明，这种γ-分泌酶与蛋白酶体竞争APP羧基末端片段的切割。此外，我们检查了蛋白激酶C（PKC）激活增加APP的非淀粉样蛋白α分泌酶裂解的机制。我们发现PKC激活不是通过改变APP交易而是通过激活负责α-分泌酶活性的特定金属蛋白酶来增加α-分泌酶的裂解。重要的是，这些蛋白酶位于反转录高尔基体网络中，这是Abeta产生的另一个已知位点。这种共定位导致APP的非淀粉样生成（α-分泌酶）和淀粉样生成（β-分泌酶）加工之间的竞争。最后，我们生成了一个淀粉样蛋白结合探针（BSB），并表明它对SP具有特异性和敏感性，并且可以穿越血脑屏障。 BSB在淀粉样蛋白生成的小鼠模型中检测到SP，因此可能对AD患者的诊断和评估有用。先前的研究进一步了解了APP的细胞内加工过程，并提供了可用于产生Abeta产生特异性抑制剂的数据。结合使用Abeta抑制剂和放射学监测AD患者斑块沉积，可以测试Abeta产量，斑块负担和临床痴呆之间的联系。

著录项

  • 作者

    Skovronsky, Daniel M.;

  • 作者单位

    University of Pennsylvania.;

  • 授予单位 University of Pennsylvania.;
  • 学科 Neurosciences.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2000
  • 页码 167 p.
  • 总页数 167
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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