COMPLEMENT AND INFLAMMATORY FACTORS IN AD PATHOGENESIS

AD 发病机制中的补体和炎症因子

• 批准号: 2873198
• 负责人: Andrea Joan Tenner
• 金额: $ 16.39万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2873198
• 关键词: Alzheimer's disease; amyloid proteins; astrocytes; complement; cytokine; enzyme linked immunosorbent assay; gene induction /repression; human tissue; inflammation; intermolecular interaction; laboratory rabbit; laboratory rat; microglia; neurons; tissue /cell culture

DESCRIPTION: (Adapted from Applicant's Abstract): Alzheimer's disease (AD) is a common dementia or loss of cognitive abilities, which is linked to the degeneration of brain tissue. This proposal is directly focussed on determining whether complement activation in AD brain triggers a pathway leading to neuropathology and dementia. Investigation of the interrelationships between biochemical reactions (C' activation) that occur and the cellular responses triggered as a result of those biochemical reactions could lead to identification of regulatory points that can subsequently be targeted for therapeutic intervention for Alzheimer disease patients. This proposal will test the hypothesis that the activation of the classical complement pathway, while resulting in lytic destruction of cells within the brain, also triggers a local inflammatory response which may contribute to the neurodegeneration and subsequent cognitive dysfunction in Alzheimer's disease. Abundant immunochemical evidence of the activation of complement in AD brain has been reported. To further assess the in vivo significance of these events, a variety of defined synthetic b-amyloid peptides, designed to represent the in vivo peptides will be assayed, via a sensitive C4 consumption assay, for their relative ability to activate complement. The results will be correlated with the ability of these peptides to form fibrils (electron microscopy) as well as variations in the secondary structure (circular dichroism) between these peptides. In addition, the effect of other proteins known to be present in the AD senile plaque (clusterin and a-antichymotrypsin ) on this activation will be assessed. In a second series of investigations, we will investigate the activation of microglia, astrocytes and neurons, before and after stimulation with the complement activation fragment C5a and/or proinflammatory cytokines. Generation of superoxide, triggering of phagocytosis, secretion of proteases, and production of cytokines and complement proteins will be determined. The ability of b-amyloid, or b-amyloid complexed with the complement initiation protein C1q to induce these inflammatory activities will also be tested, initially using in vitro primary human cell cultures when possible or primary rat cell cultures when necessary and/or appropriate. The results of these experiments will clarify the factors regulating, and the role of, complement-mediated inflammatory mechanisms in the development of neurodegeneration and cognitive dysfunction in AD. In addition, findings here should increase the understanding of other complement-mediated pathology in the CNS. Finally, the development of the in vitro model described here will allow testing of potential drugs that may modulate deleterious activities in an effort to slow or stop progression of this disease.

描述：（改编自申请人的摘要）：阿尔茨海默病（AD） 是一种常见的痴呆症或认知能力丧失，这与 脑组织的退化 该提案直接针对 确定AD脑中的补体激活是否触发了 导致神经病变和痴呆 调查 发生的生化反应（C'活化）之间的相互关系 以及这些生化反应所引发的细胞反应 反应可能导致确定监管点， 随后被靶向用于阿尔茨海默病治疗干预 患者 这项提议将检验这样一个假设，即： 经典补体途径，同时导致细胞溶解性破坏 也会引发局部炎症反应， 导致神经变性和随后的认知功能障碍， 老年痴呆症 大量的免疫化学证据表明， 补体在AD脑中的作用已有报道。 为了进一步评估体内 这些事件的意义，各种定义的合成b-淀粉样蛋白 设计用于代表体内肽的肽将通过 灵敏的C4消耗测定，用于其相对活化能力 补体 结果将与这些人的能力相关， 肽形成原纤维（电子显微镜），以及变化， 二级结构（圆二色性）之间的这些肽。 在 此外，已知存在于老年性AD中的其他蛋白质的作用 噬菌斑（丛生蛋白和α-抗胰凝乳蛋白酶）对这种激活的作用将是 评估。 在第二轮调查中，我们将调查 小胶质细胞、星形胶质细胞和神经元的激活， 用补体激活片段C5 a刺激，和/或 促炎细胞因子 产生超氧化物，引发 吞噬作用、蛋白酶分泌和细胞因子的产生， 将测定补体蛋白。 淀粉样蛋白的能力，或 b-淀粉样蛋白与补体起始蛋白C1 q复合， 这些炎症活性也将被测试，最初使用体外 原代人细胞培养物（如可能）或原代大鼠细胞培养物（如 必要和/或适当的。 这些实验的结果将阐明 补体介导的炎性细胞因子及其作用 神经变性和认知功能障碍的发展机制 在AD中。 此外，这里的发现应该增加对以下问题的理解： CNS中其他补体介导的病理学。 最后，发展 这里描述的体外模型将允许测试 可以调节有害活动以减缓或停止进展 这种疾病的