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.

通过用Abeta肽或抗ABETA被动免疫接种，淀粉样蛋白在转基因小鼠中的积累已降低。 但是，疫苗接种作用的机制知之甚少，尤其是在至少一种情况下，Abeta肽的给药并不能有效清除CNS淀粉样蛋白，即使它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。 因为尚不清楚哪种类型的ABETA是疫苗接种的目标。 这项研究的第一个目的是检查哪些ABETA物种通过疫苗接种消除。 然后，我将尝试确定疫苗接种引起的抗体的表位对原纤维反应，而不是弥漫性淀粉样蛋白。 ABETA疫苗接种的概念机制是，引起的抗Abeta抗体增强了Abeta的小胶质细胞吞噬作用，从而从大脑中清除了Abeta。但是，我们的数据和其他数据表明，外围和中枢神经系统Abeta之间的某些相互作用也影响了大脑清除Abeta。 因此，我将检查Abeta疫苗接种对血浆中ABETA水平的影响。 这两项研究将有助于理解ABETA疫苗接种疗法的分子基础，并提出了设计用于被动免疫治疗抗体的新策略。根据从这项研究中获得的证据，我将从小鼠中分离单克隆抗体显示出很高的ABETA清除效率，并将使用AD模型小鼠测试抗体在记忆障碍中的影响。