Mechanism of Amyloid Beta-Aggregation

β-淀粉样蛋白聚集机制

基本信息

批准号：
7266237
负责人：
MICHAEL Gerard ZAGORSKI
金额：
$ 27.68万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7266237
关键词：
Address Affect Alzheimer&apos s Disease Amyloid Amyloid Fibrils Amyloid beta-Protein Amyloidosis Antioxidants Area Atomic Force Microscopy Autopsy Binding Biochemistry Biological Biological Assay Brain Cell Survival Cells Cessation of life Chemicals Circular Dichroism Classification Collaborations Coupled Cultured Cells Data Deposition Deuterium Development Diffusion Electrostatics Enzymes Event Foundations Goals High Pressure Liquid Chromatography Hippocampus (Brain)Hydrogen Hydrogen Peroxide Immunotherapeutic agent Incubated Investigation Knowledge Label Lead Ligands Link Maps Measurement Methionine Methods Micelles Modeling Molecular Structure Monitor Morphology Movement Nerve Degeneration Neurofibrillary Tangles Neurologic Dysfunctions Neurons Oxidative Stress Pathologic Peptides Procedures Process Production Property Proteins Public Health Rate Reagent Recombinants Relative (related person)Relaxation Reporting Research Research Personnel Resolution Role Scientist Senile Plaques Side Site Solid Solutions Solvents Staging Standards of Weights and Measures Structural Models Structure Sulfoxide System Techniques Testing Therapeutic Thinking Thioflavin T Time Transgenic Mice Vertebral column Work abeta accumulation abeta deposition amyloid formation analytical ultracentrifugation aspartyllysine base beta pleated sheet chemical synthesis dimer extracellular in vivo inhibitor/antagonist killings medical schools molecular assembly/self assembly monomer neurotoxic neurotoxicity nuclear Overhauser enhancement oxidation peptide analog prevent programs protein aggregate research study self assembly solid state

项目摘要

DESCRIPTION (provided by applicant): The aggregation and deposition of the Abeta peptide as amyloid plaques is a key event associated with the neurodegeneration in Alzheimer's disease (AD). As one of the few research groups that has successfully studied the Abeta peptide in solution using high-resolution NMR methods, a major focus of our research is to unravel the chemical mechanisms associated with amyloid formation. The NMR approach is extremely powerful for studying proteins, in that it can detect site-specific aspects of the structures and dynamics in solution at the atomic level. In this application, we will determine the structures of early-folded Abeta aggregates, including the Abeta-derived diffusible ligands (ADDLs). Current thinking is that these soluble beta-sheet aggregates, and not the insoluble amyloid plaques, are the real culprits responsible for AD-associated neuronal death. Detailed information of the intermolecular organization within the ADDL assembly remains unknown. Our preliminary data demonstrate that NMR studies of ADDLs and other early folded beta-structures are feasible. We hypothesize that the ADDL assemblies have micelle-like properties, in which the Abeta hydrophobic C- terminus becomes clustered around the center of a micelle-like structure. Related goals will disentangle the effects of the Met35 side chain oxidation state and Abeta aggregation/amyloid formation. Although Met35ox is found in variable amounts in postmortem amyloid plaques, the chemistry and biological role of these oxidative events remains unknown. This work will provide a solid chemical foundation for the relationship between the Met35 oxidative state and the oxidative stress events associated with Alzheimer's disease, such as whether or not the longer Abeta(1-42) may be more reactive toward reactive oxidative species (ROS) in vivo. Relevance to Public Health: Knowledge of the chemical mechanisms of Abeta aggregation, combined with our unique use of NMR, will provide critical atomic level details that will eventually lead to better therapeutic approaches to prevent amyloid formation in Alzheimer's disease.

描述（由申请人提供）：Abeta 肽作为淀粉样斑块的聚集和沉积是与阿尔茨海默病（AD）中的神经变性相关的关键事件。作为少数几个使用高分辨率 NMR 方法成功研究溶液中 Abeta 肽的研究小组之一，我们研究的主要重点是揭示与淀粉样蛋白形成相关的化学机制。核磁共振方法对于研究蛋白质来说非常强大，因为它可以在原子水平上检测溶液中结构和动力学的特定位点方面。在此应用中，我们将确定早期折叠的 Abeta 聚集体的结构，包括 Abeta 衍生的可扩散配体 (ADDL)。目前的想法是，这些可溶性β-折叠聚集体，而不是不溶性淀粉样蛋白斑块，才是导致 AD 相关神经元死亡的真正罪魁祸首。 ADDL 组件内分子间组织的详细信息仍然未知。我们的初步数据表明，ADDL 和其他早期折叠 β 结构的 NMR 研究是可行的。我们假设 ADDL 组件具有胶束样特性，其中 Abeta 疏水性 C 末端聚集在胶束样结构的中心周围。相关目标将阐明 Met35 侧链氧化态和 Abeta 聚集/淀粉样蛋白形成的影响。尽管在死后淀粉样斑块中发现了不同数量的 Met35ox，但这些氧化事件的化学和生物学作用仍然未知。这项工作将为 Met35 氧化状态与阿尔茨海默病相关氧化应激事件之间的关系提供坚实的化学基础，例如较长的 Abeta(1-42) 是否可能对活性氧化物质 (ROS) 更具反应性体内。与公共健康的相关性：对 Abeta 聚集的化学机制的了解，结合我们对 NMR 的独特使用，将提供关键的原子水平细节，最终将导致更好的治疗方法来预防阿尔茨海默病中淀粉样蛋白的形成。