Elucidating the mechanism of amyloid-beta's pathological aggregation

阐明β淀粉样蛋白病理聚集机制

• 批准号: 8774689
• 负责人: Pieter Ernst Smith
• 金额: $ 0.79万
• 依托单位: WEIZMANN INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774689
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid fibers; Autopsy; Behavior; Biological; Biological Models; Brain; Caregivers; Cell Culture Techniques; Cell Nucleus; Chemicals; Clinical; Data Set; Deposition; Detection; Development; Diffusion; Dimensions; Disease; Elderly; Employee Strikes; Environment; Equilibrium; Etiology; Evolution; Frequencies; Goals; Homo; Human; In Vitro; Investigation; Laboratories; Life; Measurement; Measures; Medical; Methodology; Methods; Minority; Modification; Molecular; NMR Spectroscopy; Nature; Neurodegenerative Disorders; Nuclear; Onset of illness; Oocytes; Pathology; Patients; Peptides; Phenotype; Play; Process; Productivity; Property; Public Health; Quality of life; Radial; Relaxation; Role; Sampling; Scheme; Severities; Signal Transduction; Site; Solutions; Speed; Staging; Structure; Symptoms; System; TOCSY; Techniques; Time; Transgenic Organisms; United States; Variant; Xenopus laevis; Xenopus oocyte; abeta accumulation; abstracting; age related; aggregation pathway; aqueous; cognitive function; conformer; cytotoxicity; extracellular; in vivo; innovation; insight; interest; molecular size; monomer; mouse model; polymerization; research study; spectroscopic imaging; tool

7. Project summary/Abstract Alzheimer's disease (AD), the most common neurodegenerative disorder, is an age-dependent disorder resulting in progressive loss of cognitive function. It affects more than 4 million people in the United States and is therefore a highly relevant factor in the elderly's quality of life. The symptoms of the disease strongly correlate with the presence of transiently formed and soluble aggregates of amyloid-β (Aβ) in the brains of AD patients. Because of the relevance Alzheimer's to public health, there is substantial interest in understanding the molecular mechanism of AD and treating the disease. Nevertheless, the short-lived nature of the Aβ soluble intermediates formed during the course of its pathological aggregation presents a formidable challenge to the traditional techniques used for the investigation of biological molecules. Although progress has been made in studying these molecules, by making slight chemical modifications that increase their stability, for example, it is not known whether the molecular behavior observed in these studies is completely relevant to the behavior of Aβ in humans. In the Frydman lab techniques have been developed that allow the fast characterization of features of biological molecules relevant to their behavior (structure and dynamics). We propose to use these techniques, a suite of ultrafast NMR experiments, to investigate the structure and dynamics of Aβ as it undergoes aggregation. Ultrafast TOCSY and STD-TOCSY experiments will be used to probe the interaction between Aβ monomers and oligomers during the aggregation process. The diffusive dynamics of the system will be probed by ultrafast DOSY experiments, which separates resonances according to the hydrodynamic radii associated with the chemical sites to which they belong. Further functional insights will also be gained from site-resolved longitudinal relaxation measurements, which reveal the mobility of molecular fragments-and hence their degree of polymerization. This proposal aims to uncover detailed structural information about Aβ's folded monomeric state, which is believed to play a crucial role in the formation of a nucleus for Aβ's aggregation. In aqueous solution, folded conformers of Aβ undergo conformational exchange with its random coil state. Using the innovative selective dynamic recoupling (SDR) technique that I have developed, the chemical shifts of folded Aβ conformers will be revealed, which can be used to probe their structures. The in vivo behavior of Aβ in a cellular environment is believed to play a significant role in its pathology. I plan to uncover detailed information on the intracellular behavior of Aβ by performing NMR experiments in living Xenopus laevis oocytes.

7.项目概要/摘要 阿尔茨海默病（AD）是最常见的神经退行性疾病，是一种年龄依赖性疾病， 导致认知功能逐渐丧失的疾病。它影响了400多万人， 因此，它是老年人生活质量的一个高度相关因素。的症状 疾病与淀粉样蛋白-β的瞬时形成和可溶性聚集体的存在密切相关 （Aβ）在AD患者的大脑中。由于阿尔茨海默氏症与公共卫生的相关性， 对了解AD的分子机制和治疗该疾病有着浓厚的兴趣。 然而，在其过程中形成的Aβ可溶性中间体的短暂性质， 病理性聚集对用于免疫学的传统技术提出了巨大挑战。 生物分子的研究。尽管在研究这些分子方面取得了进展， 进行轻微的化学修饰，以增加其稳定性，例如，不知道是否 这些研究中观察到的分子行为与Aβ在人体中的行为完全相关。在 已经开发了Frydman实验室技术，该技术允许快速表征 与其行为（结构和动力学）相关的生物分子。我们建议使用这些 技术，一套超快核磁共振实验，研究Aβ的结构和动力学，因为它 经历聚合。超快TOCSY和STD-TOCSY实验将用于探测 在聚集过程中Aβ单体和低聚物之间的相互作用。扩散 系统的动力学将通过超快DOSY实验来探测，该实验将共振分离 根据与它们所属的化学位点相关的流体动力学半径。进一步 还将从现场分辨纵向弛豫测量中获得功能性见解， 揭示了分子碎片的流动性，从而揭示了它们的聚合度。这项建议 旨在揭示Aβ折叠单体状态的详细结构信息，据信 在形成Aβ聚集的核中起着至关重要的作用。在水溶液中，折叠 Aβ的构象与其无规卷曲状态进行构象交换。使用创新的 选择性动态再偶联（SDR）技术，我已经开发，折叠Aβ的化学位移 构象将被揭示，这可以用来探测它们的结构。Aβ在a 认为细胞环境在其病理学中起重要作用。我计划揭开 通过在活的非洲爪蟾中进行NMR实验获得Aβ细胞内行为的信息 卵母细胞