STRUCTURE AND REDOX CHEMISTRY OF TRUNCATED AMYLOID AGGREGATES

截短的淀粉样蛋白聚集体的结构和氧化还原化学

• 批准号: 7954473
• 负责人: PIERRE KENNEPOHL
• 金额: $ 0.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954473
• 关键词: Address; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Attention; Behavior; Binding; Brain; Chemistry; Computer Retrieval of Information on Scientific Projects Database; Event; Funding; Grant; Image; In Vitro; Institution; Ions; Membrane Proteins; Metals; Methionine; Mus; Oxidation-Reduction; Physiological; Proteins; Research; Research Personnel; Resources; Role; Source; Structure; Techniques; Transition Elements; United States National Institutes of Health; abeta accumulation; brain tissue; in vivo; meetings; oxidation; protein aggregation; protein misfolding; structural biology; synchrotron radiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have been exploring the behaviour of amyloid-beta (Ab) and several truncated forms of the protein (Ab1-16, Ab1-38, Ab1-42) in the presence of redox-active transition metal ions (Fe, Cu) to explore the relationship between metals redox chemistry and Ab aggregation. Although this problem is being addressed in many different way our approach has focused on the role of methionine oxidation as a trigger for protein misfolding and subsequent aggregation. We have recently obtained the first STXM images at the S K-edge (as well as the Cu and Fe L-edges) of mouse brains to explore the relationship between physiological changes in brain tissue and whether these can be related to specific changes observed in vitro. The role of amyloid-beta aggregation in the progression of Alzheimers? disease has received significant attention. Although several possible mechanisms of aggregation have been postulated, the specifics have yet to be elucidated. One of the postulated mechanisms for protein aggregation in vivo posits that oxidation of the sole methionine in Ab begins a cascade of events, which eventually results in Ab aggregation. This redox trigger mechanism would involve Met oxidation from binding of redox-active transition metals to the membrane protein. We have been exploring this postulated mechanism using a wide range of techniques, focusing much of our effort on determining whether a correlation between methionine oxidation and transition metal (specifically Cu(II) and/or Fe(III)) reduction can be determined both in vitro and in vivo.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们一直在研究淀粉样β蛋白(AB)及其几种截断形式的蛋白质(AB1-16、AB1-38、AB1-42)在氧化还原活性过渡金属离子(Fe、Cu)存在下的行为，以探索金属氧化还原化学与Ab聚集之间的关系。虽然这个问题正以许多不同的方式解决，但我们的方法侧重于蛋氨酸氧化作为蛋白质错误折叠和随后聚集的触发器所起的作用。我们最近首次获得了小鼠大脑S K边(以及铜和铁L边)的扫描电子显微镜图像，以探索脑组织生理变化之间的关系，以及这些变化是否与体外观察到的特定变化有关。淀粉样β蛋白聚集在阿尔茨海默病进展中的作用？疾病已经受到了极大的关注。虽然已经提出了几种可能的聚集机制，但具体细节尚未阐明。蛋白质在体内聚集的假设机制之一是，抗体中唯一的蛋氨酸氧化开始一系列事件，最终导致抗体聚集。这种氧化还原触发机制将涉及Met氧化，从氧化还原活性的过渡金属结合到膜蛋白上。我们一直在使用广泛的技术探索这一假设的机制，重点是确定蛋氨酸氧化和过渡金属(特别是铜(II)和/或铁(III))还原之间的相关性是否可以在体外和体内确定。