Profile of beta-amyloid in response to beta-amyloid vacc

β-淀粉样蛋白对 β-淀粉样蛋白疫苗的反应概况

• 批准号: 6479486
• 负责人: YASUJI MATSUOKA
• 金额: $ 7.48万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479486
• 关键词: Alzheimer's disease; active immunization; amyloid proteins; amyloidosis; antigen antibody reaction; brain; brain disorder chemotherapy; conformation; enzyme linked immunosorbent assay; genetically modified animals; histochemistry /cytochemistry; human genetic material tag; laboratory mouse; mass spectrometry; microglia; monoclonal antibody; neuritic plaques; phagocytosis; plasma; protein protein interaction; protein structure; protein structure function; vaccines

The accumulation of amyloid in transgenic mice has been reduced by vaccination with either Abeta peptide or passive immunization with anti-Abeta. However, the mechanism by which vaccination works is poorly understood, especially as in at least one case, Abeta peptide administration did not clear CNS amyloid efficiently, even though it did correct cognitive impairment associated with amyloid accumulation in these mice. As it is not clear what type of Abeta is the target for vaccination. The first aim of this study is to examine which Abeta species are eliminated by vaccination. I will then attempt to identify which epitope of antibodies elicited by vaccination respond to fibrillar as opposed to diffuse amyloid. The conceptional mechanism of Abeta vaccination is that elicited anti-Abeta antibodies enhance microglial phagocytosis of Abeta leading to the clearance of Abeta from the brain. However, our, and other's data suggest that some interplay between peripheral and CNS Abeta also influences clearance of Abeta from the brain. Therefore, I will examine the effects of Abeta vaccination on Abeta levels in plasma. These two studies will aid in understanding the molecular basis of Abeta vaccination therapy, and suggest new strategies to design an antibody for passive immunization therapy. Based on evidence to be obtained from this study, I will isolate monoclonal antibodies from the mouse showed high Abeta clearance efficiency, and will test the effects of antibody in memory impairment using AD model mice.

通过接种 Abeta 肽或抗 Abeta 被动免疫，转基因小鼠中淀粉样蛋白的积累已减少。 然而，人们对疫苗接种的作用机制知之甚少，特别是在至少一种情况下，尽管 Abeta 肽确实纠正了这些小鼠中与淀粉样蛋白积累相关的认知障碍，但它并没有有效清除 CNS 淀粉样蛋白。 由于尚不清楚疫苗接种的目标是什么类型的 Abeta。 这项研究的首要目的是检查哪些 Abeta 物种可以通过疫苗接种消除。 然后，我将尝试确定疫苗接种引起的抗体的哪些表位对纤维状而不是弥漫性淀粉样蛋白有反应。 Abeta 疫苗接种的概念机制是引发的抗 Abeta 抗体增强小胶质细胞对 Abeta 的吞噬作用，导致 Abeta 从大脑中清除。然而，我们和其他人的数据表明，外周 Abeta 和 CNS Abeta 之间的一些相互作用也会影响 Abeta 从大脑中的清除。 因此，我将研究 Abeta 疫苗接种对血浆 Abeta 水平的影响。 这两项研究将有助于了解 Abeta 疫苗接种疗法的分子基础，并提出设计用于被动免疫疗法的抗体的新策略。基于从这项研究中获得的证据，我将从表现出高Abeta清除效率的小鼠中分离出单克隆抗体，并将使用AD模型小鼠来测试抗体对记忆障碍的影响。