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肽作为淀粉样蛋白斑的聚集和沉积是与阿尔茨海默氏病（AD）神经变性有关的关键事件。作为使用高分辨率NMR方法成功研究溶液中ABETA肽的少数研究小组之一，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。 NMR方法对于研究蛋白质非常有力，因为它可以检测原子水平溶液中结构和动态的位点特异性方面。在此应用程序中，我们将确定早期折叠的ABETA聚集体的结构，包括ABETA衍生的扩散配体（ADDL）。目前的思想是，这些可溶性的β-骨架聚集体，而不是不溶性淀粉样蛋白斑块，是负责广告相关神经元死亡的真正罪魁祸首。 ADDL组件中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组件具有类似胶束的特性，其中Abeta疏水C-末端聚集在胶束样结构的中心周围。相关目标将消除MET35侧链氧化状态和Abeta聚集/淀粉样蛋白形成的影响。尽管Met35ox在验化后淀粉样斑块中的变量中发现，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氧化状态与与阿尔茨海默氏病有关的氧化应激事件之间的关系提供固体化学基础，例如在体内较长的ABETA（1-42）是否可能对反应性氧化物种（ROS）更具反应性。与公共卫生的相关性：了解Abeta聚集的化学机制的知识，再加上我们对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，以防止阿尔茨海默氏病中的淀粉样蛋白形成。