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Complement Activation in Alzheimer's disease: Contribution of C5a and its receptor CD88.

机译：阿尔茨海默氏病的补体激活：C5a及其受体CD88的贡献。

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摘要

It is estimated that there are 5.4 million people affected by Alzheimer's disease (AD) in the United States with no approved disease modifying treatments to prevent or treat cognitive deficits. Furthermore, drugs that treat symptoms are effective for only a short period of time. Recent disappointing results from anti-amyloid beta (Abeta) therapies and recent intriguing results using an anti-Abeta antibody, MABT, which enhances an anti-inflammatory phagocytic response reflects the need for further investigation of specific modulators of the inflammatory response. The complement cascade (C') is a critical effector mechanism of the innate immune system for quickly clearing pathogens and directing the adaptive immune response. The beneficial and detrimental roles of C' in AD are becoming more established as well as the relationship of C' with other aspects of inflammation (in the periphery as well as the central nervous system (CNS)) making a thorough understanding of the role of complement in the disease more critical for therapeutic design. For example, complement components have been found to synergize with other innate immune proteins, such as Toll-Like Receptors (TLRs), which are known to also interact with fibrillar amyloid in AD associated plaques. While mouse models are critical for preclinical investigation, many critical differences between the mouse and human immune system make disease modeling difficult. C5a, generated as a consequence of complement activation, is a potent pro-inflammatory mediator of the C'. Evidence is accruing that a pharmacological approach using an antagonist to CD88, a C5a receptor (C5aR), will prevent a detrimental chronic inflammatory state produced by C5a, while preserving beneficial effects of other complement components (C1q and C3b). We hypothesize that prevention of C5aR-induced damage by immune mediators to neurons surrounding the amyloid plaques will slow progression of neurodegenerative disease. In addition to testing the hypothesis directly by using a pharmacological approach I used mouse models of AD lacking C5aR (CD88) to determine if the inflammatory response is diminished and disease progression is slowed by the lack of the receptor, and used mouse models of AD overproducing the C5a protein to determine whether this accelerates disease progression. Finally, we propose the generation of a new mouse model of neuroinflammatory diseases that will have greater complement activity and more accurately reflect the activation of the complement cascade in humans.;Together, my dissertation research adds to our knowledge of the interactions between one aspect of inflammation in Alzheimer's disease.
机译：据估计，在美国，有540万人受阿尔茨海默氏病（AD）的影响，没有批准用于预防或治疗认知缺陷的疾病改良疗法。此外，治疗症状的药物仅在短时间内有效。抗淀粉样蛋白（Abeta）治疗的最新令人失望的结果以及使用抗Abeta抗体MABT的令人振奋的结果，增强了抗炎吞噬反应，反映出需要进一步研究炎症反应的特定调节剂。补体级联（C'）是先天免疫系统的关键效应器机​​制，可快速清除病原体并指导适应性免疫反应。 C'在AD中的有益和有害作用变得越来越明确，C'与炎症的其他方面（在周围以及中枢神经系统（CNS）中）之间的关系也变得更加透彻，从而使人们对C'的作用有了透彻的了解。在疾病中的补体对于治疗设计更为关键。例如，已经发现补体成分与其他先天免疫蛋白例如Toll样受体（TLR）协同作用，已知这些蛋白也与AD相关斑块中的原纤维淀粉样蛋白相互作用。尽管小鼠模型对于临床前研究至关重要，但是小鼠与人类免疫系统之间的许多关键差异使疾病建模变得困难。由于补体激活而产生的C5a是C'的有效促炎介质。有证据表明，使用CD88拮抗剂C5a受体（C5aR）的药理学方法将预防C5a产生的有害的慢性炎症状态，同时保留其他补体成分（C1q和C3b）的有益作用。我们假设免疫介体对淀粉样蛋白斑块周围神经元的免疫介导阻止C5aR诱导的损伤将减缓神经退行性疾病的进展。除了使用药理学方法直接检验假设外，我还使用了缺乏C5aR（CD88）的AD小鼠模型来确定炎症反应是否减弱以及缺乏受体而减缓了疾病进展，并使用了AD过量生产的小鼠模型C5a蛋白，以确定其是否加速疾病进展。最后，我们提出了一种新的神经炎性疾病小鼠模型的产生，该模型将具有更强的补体活性，并更准确地反映人类补体级联的激活。；总的来说，我的论文研究增加了我们对人类一方面的相互作用的认识。阿尔茨海默氏病的炎症。

著录项

  • 作者

    Cole, Tracy Ann.;

  • 作者单位

    University of California, Irvine.;

  • 授予单位 University of California, Irvine.;
  • 学科 Biology Neuroscience.;Health Sciences Immunology.;Health Sciences Aging.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 189 p.
  • 总页数 189
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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