Mimicry of Amyloid Oligomers

淀粉样蛋白寡聚物的模拟

• 批准号: 8413852
• 负责人: JAMES S NOWICK
• 金额: $ 28.13万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413852
• 关键词: Adopted; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Antibodies; Area; Basic Science; Behavior; Biochemical; Biological; Biological Models; Biophysics; Cells; Chemical Models; Creutzfeldt-Jakob Syndrome; Dendritic Spines; Development; Disease; Elements; Goals; Huntington Disease; Hydrogen Bonding; Hydrophobic Interactions; Inherited; Knowledge; Laboratories; Lead; Long-Term Depression; Long-Term Potentiation; Methodology; Modeling; Mus; NMR Spectroscopy; Neurobiology; Neurodegenerative Disorders; Neurons; Peptides; Prion Diseases; Prions; Process; Property; Proteins; Rattus; Research; Slice; Sorting - Cell Movement; Structure; Synapses; Techniques; Testing; X-Ray Crystallography; amyloid structure; beta pleated sheet; crosslink; density; dimer; falls; insight; interest; mimicry; molecular assembly/self assembly; neurotoxic; peptidomimetics; protein aggregate; protein aggregation; protein function; self assembly; tool

DESCRIPTION (provided by applicant): The aggregation of peptides and proteins is central to many devastating neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, and the prion diseases. Although amyloid fibrils have long been viewed as the hallmark of Alzheimer's and other neurodegenerative diseases, the oligomers formed by amyloidogenic peptides have begun to emerge as the more important neurotoxic species involved in Alzheimer's and other neurodegenerative diseases. The fibrils adopt layered beta-sheet structures. Although the structures of the oligomers are only beginning to emerge, they appear to also involve beta-sheet formation and may involve layering and related hydrophobic interactions. The development of robust model systems to mimic the structure of amyloid oligomers offers the promise of not only providing insights into the structures and biological activities of amyloid oligomers, but also providing new tools with which to control peptide and protein interactions involving beta-sheet formation. This project will approach the problem of stabilizing small oligomeric beta-sheets by developing interstrand and intersheet crosslinks tailored to stabilize interactions between beta-sheets. These crosslinks will be developed using macrocyclic beta-sheets developed in the PI's laboratory. The macrocyclic beta-sheets form hydrogen-bonded dimers that further self-assemble through hydrophobic interactions to form sandwich-like structures. Intersheet crosslinks will be developed to stabilize the layered structures and control self-assembly. Intrasheet crosslinks will be developed to achieve parallel beta-sheet structures. Macrocyclic beta-sheets containing these crosslinks will be used to mimic the structure of the amyloid beta-peptide dimer. The structures of the mimics of amyloid oligomers will be evaluated by NMR spectroscopy, X-ray crystallography, and other biophysical techniques. The ability of these molecules and molecular assemblies to mimic amyloid beta-peptide oligomers will be evaluated by using oligomer-specific antibodies and neuronal cells to compare their behavior to natural amyloid beta-peptide oligomers. The effect of promising amyloid oligomer mimics on long-term potentiation, long-term synaptic depression, and dendritic spine density at synapses will be studied in mouse hipocampal slices and rat organotypic slices.

描述（由申请人提供）：肽和蛋白质的聚集是许多毁灭性神经退行性疾病的核心，包括阿尔茨海默氏病，亨廷顿氏病和病毒疾病。尽管长期以来，淀粉样蛋白原原纤维一直被视为阿尔茨海默氏症和其他神经退行性疾病的标志，但淀粉样蛋白生成肽形成的低聚物已经开始出现，因为它是涉及阿尔茨海默氏症和其他神经变性疾病的更重要的神经毒性物种。原纤维采用分层的beta表结构。尽管低聚物的结构才刚刚开始出现，但它们似乎也涉及β-片状形成，并且可能涉及分层和相关的疏水相互作用。模仿淀粉样蛋白低聚物结构的强大模型系统的开发不仅提供了对淀粉样蛋白低聚物的结构和生物学活性的见解，还提供了用于控制涉及Beta-seet形成的肽和蛋白质相互作用的新工具。该项目将解决稳定小寡聚beta表的问题，通过开发用于稳定β表之间相互作用的链间和互链交联。这些交叉链接将使用PI实验室中开发的大环β-元式开发。大环β型表形成氢键二聚体，通过疏水相互作用进一步自组装，形成类似三明治的结构。将开发互链交联来稳定分层结构并控制自组装。 Intrasheet交叉链接将开发以实现并行的Beta-sheet结构。包含这些交联的大环ββ将用于模仿淀粉样蛋白β-肽二聚体的结构。淀粉样蛋白低聚物的模拟物结构将通过NMR光谱，X射线晶体学和其他生物物理技术进行评估。这些分子和分子组件对模仿淀粉样β-肽肽寡聚物的能力将通过使用低聚物特异性抗体和神经元细胞进行评估，以将其行为与天然淀粉样β肽肽寡聚物进行比较。有希望的淀粉样蛋白低聚物模拟物对突触时长期增强，长期突触抑制和树突状脊柱密度的影响将在小鼠Hipocampal切片和大鼠器官型切片中进行研究。