Solid State NMR Structural Analysis of Oligomeric Alzheimer's Beta-Amyloid Peptide

寡聚阿尔茨海默病 β-淀粉样肽的固态 NMR 结构分析

• 批准号: 9265374
• 负责人: Anant Krishna Paravastu
• 金额: $ 28.74万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265374
• 关键词: Address; Alzheimer disease detection; Alzheimer' s Disease; Amino Acid Sequence; Amino Acids; Amyloid Fibrils; Amyloid Proteins; Amyloid beta-Protein; Biochemical; Brain; Charge; Chemicals; Clinic; Computer Simulation; Data; Deposition; Diagnostic; Disease; Early Diagnosis; Event; Florida; Genetic; Hand; Isotope Labeling; Knowledge; Label; Lead; Maps; Measurement; Micelles; Modeling; Molecular; Molecular Conformation; Molecular Sieve Chromatography; Nanostructures; Neurons; Pathologic; Pathology; Pathway interactions; Physiological; Play; Proteins; Reporting; Research; Role; Sampling; Severity of illness; Signal Transduction; Site; Sodium; Spectrum Analysis; Structural Models; Structure; Testing; Therapeutic; Torsion; Toxic effect; Universities; Vertebral column; Work; X-Ray Crystallography; abeta oligomer; base; design; experimental study; model design; nanostructured; neuron loss; public health relevance; self assembly; solid state nuclear magnetic resonance; tool; two-dimensional

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) research has traditionally focused on amyloid fibrils found in plaque deposits in the brain, but recent evidence suggests that oligomers of Alzheimer's beta-amyloid peptides play a more significant role in initiating AD pathology. The long-term objective of this project is, through characterizing Abeta oligomer structures, answer fundamental questions about pathways of A beta self-assembly and how these pathways could be controlled as strategies for designing therapeutics. The proposed research addresses major challenges related to oligomer stability and structural homogeneity, which have hindered oligomer structural characterization to date. We will determine the structure of a 150 kDa Abeta (1-42) oligomer by integrating solid state nuclear magnetic resonance (ssNMR) spectroscopy with computational modeling. Specifically, we will 1) define secondary structure and sidechain proximity across the amino acid sequence; 2) Determine alignments between neighboring beta -strands and conformations of non- beta -strand regions; and 3) Model the structure of the Abeta (1-42) oligomer based on the ssNMR data. The structural information obtained in this project will help characterize early events in Abeta self-assembly and may lead to diagnostic tools for early detection of Alzheimer's disease and therapeutic strategies that exploit differences in oligomer and fibril assembly pathways.

描述(申请人提供)：阿尔茨海默病(AD)的研究传统上集中在大脑斑块沉积中发现的淀粉样纤维，但最近的证据表明，阿尔茨海默病的β-淀粉样多肽的寡聚体在启动AD病理过程中发挥了更重要的作用。该项目的长期目标是，通过表征Aβ齐聚物的结构，回答有关Aβ自组装途径的基本问题，以及如何控制这些途径作为设计治疗的策略。这项拟议的研究解决了与齐聚物稳定性和结构同质性有关的主要挑战，这些挑战到目前为止阻碍了低聚物结构表征。我们将结合固体核磁共振波谱和计算模型来确定150 kDa阿贝塔(1-42)齐聚物的结构。具体地说，我们将1)定义氨基酸序列上的二级结构和侧链邻近程度；2)确定相邻β链和非β链区域的构象之间的比对；以及3)基于单核磁共振数据建模Abeta(1-42)低聚物的结构。在这个项目中获得的结构信息将有助于表征Abeta自组装的早期事件，并可能导致早期检测阿尔茨海默病的诊断工具和利用寡聚体和原纤维组装路径差异的治疗策略。