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The contribution of the complement system in the development of Alzheimer's disease pathology and cognitive dysfunction.

机译：补体系统在阿尔茨海默氏病病理和认知功能障碍发展中的作用。

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摘要

Alzheimer's Disease (AD), a progressive neurodegenerative disorder characterized by amyloid-beta and hyperphosphorylated tau accumulation, and neuronal loss, is associated with aging. Genetic studies have contributed to the development of the amyloid cascade hypothesis, as a cause of disease development. An immune presence, including activated glia and complement deposition, in reaction to amyloid buildup, has produced the hypothesis that complement activation is a substantial component in AD progression.;Most AD mouse models lack substantial neuronal degeneration or loss, which could impact their learning impairment and thus their usefulness as a model for human AD. Previous experiments, demonstrated weaker mouse complement activation, in response to fibrillar Abeta (fAbeta) compared with human complement, possibly due to differences in human vs. mouse C1q A chain. It was hypothesized that weaker complement activation could result in lower neuronal loss. Thus, the A chain of mouse complement component C1q, was altered to mimic human C1q. However, increased fAbeta-C1q interaction was not observed after the modification. The subsequently published crystal structure of C1q globular head domains, suggested that a similar 3-dimensional arrangement of amino acids on the B chain subunit provides sufficient interaction between mouse C1q and fAbeta, without the A chain contribution. One complement activation product, C5a, is an initiator of inflammation. Analysis of AD model mice revealed that CNS expression of CD88, a cellular receptor for C5a, increases with age and is localized around Abeta plaques. Targeting C5a activity, with a CD88 antagonist (PMX205) for 12 weeks, resulted in a significant reduction in thoiflavine positive Abeta plaques and activated glia. Additionally, reductions in hyperphosphorylated tau (in 3xTg mice) and neuronal damage in the hippocampus (in Tg2576 mice) were observed. Reductions in pathology were correlated with improved contextual memory in Tg2576 mice. Treatment with PMX205, demonstrated that CD88 in microglia surrounding plaques was reduced in parallel with reduced plaque load. Importantly, the treatment does not negatively interfere with complement components which have been suggested to be protective in other AD models. These results suggest, inhibition of CD88 may serve as a therapy towards AD.
机译：阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征在于淀粉样β和过度磷酸化的tau积累以及神经元丢失，与衰老相关。遗传学研究促进了淀粉样蛋白级联假说的发展，这是疾病发展的原因。对淀粉样蛋白积累的反应包括激活的神经胶质细胞和补体沉积在内的免疫存在产生了以下假设：补体激活是AD进展中的重要组成部分。大多数AD小鼠模型缺乏实质性神经元变性或丧失，这可能会影响其学习障碍因此，它们作为人类AD模型的有用性。先前的实验表明，与人补体相比，对原纤维Abeta（fAbeta）的小鼠补体激活较弱，这可能是由于人与鼠C1q A链的差异所致。据推测，较弱的补体激活可导致较低的神经元损失。因此，小鼠补体成分C1q的A链被改变以模仿人C1q。但是，修改后未观察到增加的fAbeta-C1q相互作用。随后发布的C1q球状头部结构域的晶体结构表明，B链亚基上氨基酸的类似3维排列提供了小鼠C1q和fAbeta之间的充分相互作用，而没有A链的贡献。一种补体激活产物，C5a，是炎症的引发剂。对AD模型小鼠的分析表明，CD88（C5a的一种细胞受体）的CNS表达随年龄增长而增加，并位于Abeta斑块附近。用CD88拮抗剂（PMX205）靶向C5a活性持续12周，导致胸黄素阳性Abeta斑块和胶质细胞活化显着减少。此外，观察到高磷酸化的tau减少（在3xTg小鼠中）和海马的神经元损伤（在Tg2576小鼠中）。病理学的减少与Tg2576小鼠的情境记忆改善有关。用PMX205处理表明，减少斑块负荷的同时减少了小胶质细胞周围斑块中的CD88。重要的是，该治疗不会对补体成分产生负面影响，而补体成分在其他AD模型中被认为具有保护作用。这些结果表明，抑制CD88可以作为针对AD的疗法。

著录项

  • 作者

    Ager, Rahasson Roland.;

  • 作者单位

    University of California, Irvine.;

  • 授予单位 University of California, Irvine.;
  • 学科 Biology Molecular.;Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 194 p.
  • 总页数 194
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:19

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