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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由申请人提供）：阿尔茨海默病（AD）研究传统上集中于大脑斑块沉积物中发现的淀粉样原纤维，但最近的证据表明阿尔茨海默病β-淀粉样肽的寡聚体在引发AD病理学中发挥更重要的作用。该项目的长期目标是通过表征 Abeta 寡聚物结构，回答有关 Abeta 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。拟议的研究解决了与低聚物稳定性和结构同质性相关的主要挑战，这些挑战迄今为止阻碍了低聚物结构表征。我们将通过将固态核磁共振 (ssNMR) 光谱与计算模型相结合来确定 150 kDa Abeta (1-42) 低聚物的结构。具体来说，我们将 1) 定义氨基酸序列的二级结构和侧链邻近度； 2)确定相邻β链和非β链区域构象之间的比对； 3) 根据 ssNMR 数据对 Abeta (1-42) 低聚物的结构进行建模。该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，并可能产生用于早期检测阿尔茨海默病的诊断工具以及利用寡聚物和原纤维组装途径差异的治疗策略。