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Characterizing Alzheimer's Amyloid-beta Oligomer Structures by Solid-State NMR and Cryo-Electron Microscopy

通过固态核磁共振和冷冻电子显微镜表征阿尔茨海默病β淀粉样蛋白寡聚物结构

基本信息

批准号：
10455850
负责人：
Anant Krishna Paravastu
金额：
$ 162.31万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10455850
关键词：
3-Dimensional Alzheimer&apos s Disease Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Amyloid Amyloid Fibrils Amyloid beta-42 Amyloid beta-Protein Antibodies Antibody Therapy Biological Biological Assay C-terminal Complement Complement 2 Computer Models Cryoelectron Microscopy Data Detergents Diagnostic Disease Disease model Early Diagnosis Electron Microscopy Environment Exhibits Experimental Designs Failure Future Hydrophobicity Image Isotope Labeling Knowledge Lipids Machine Learning Maps Measurable Measurement Measures Membrane Methods Micelles Modeling Modification Molecular Weight Mutation Nanostructures Nuclear Nuclear Magnetic Resonance Pathologic Pathway interactions Peptides Pharmaceutical Preparations Preparation Proteins Protocols documentation Reporting Research Resolution Sampling Series Sodium Chloride Structural Models Structure Techniques Testing Therapeutic Ultracentrifugation Vertebral column Work abeta accumulation abeta oligomer aggregation pathway amyloid formation amyloid structure beta pleated sheet design experimental study gamma secretase image processing improved in vivo magnetic field microscopic imaging mimetics nanoparticle predictive test prevent proteoliposomes solid state nuclear magnetic resonance structural biology targeted treatment two-dimensional

项目摘要

PROJECT SUMMARY In Alzheimer's disease (AD) research, much focus has been on oligomeric assemblies of the amyloid-β (Aβ) peptide (a small protein). Oligomers are small nanoparticles produced by the aggregation of 50 or fewer peptide molecules. Peptide aggregation most readily produces amyloid fibrils, and it is a mystery what prevents some oligomers from aggregating further into fibrils. Even within oligomeric and fibrillar aggregate classes, peptide aggregates with a range of structures have been detected. Nevertheless, structural biology methods require stable and structurally homogeneous samples to achieve high-resolution information. To elucidate what oligomer structures are possible and which of these structures should be targeted by AD therapies, experiments are designed to understand Aβ assembly in general terms. Preliminary data show that it is possible to produce stable homogeneous samples of a 150 Aβ oligomer (32 Aβ peptide molecules) and study its structure using solid-state nuclear magnetic resonance (NMR) and electron microscopy (EM). Notably, the 150 kDa oligomer structure is unlike any previously understood Aβ assembly, and this observation presents a unique opportunity to probe how oligomer and fibril structures may differ. The project will pursue high-resolution atomic-level characterization of the 150 kDa oligomer by integrating solid-state NMR, cryo-EM, and computational modeling. The work further seeks to generalize understanding of Aβ assembly mechanisms by testing hypothesized assembly pathways inspired by the 150 kDa oligomer. The proposed work will: achieve a 3-dimensional image of the 150 kDa oligomer using cryo-EM (Aim 1); measure complementary atomic-level structural constraints with solid-state NMR (Aim 2); and test mechanistic hypotheses to produce new oligomers compatible with EM and NMR workflows (Aim 3). Knowledge of what oligomer structures are possible for Aβ (and how to isolate specific structures) is critical for developing new Alzheimer's therapeutics, implementing strategies for early detection, and designing mechanistic studies in disease models.

项目摘要在阿尔茨海默病（AD）的研究中，淀粉样蛋白β（Aβ）的寡聚体组装体一直是研究的重点肽（一种小蛋白质）。寡聚体是由50个或更少的肽聚集产生的小纳米颗粒分子。肽聚集最容易产生淀粉样纤维，是什么阻止了一些淀粉样纤维的形成是一个谜。低聚物进一步聚集成原纤维。即使在低聚物和纤维状聚集体类别中，已经检测到具有一系列结构的聚集体。然而，结构生物学方法需要稳定和结构均匀的样品，以实现高分辨率的信息。为了阐明寡聚体结构是可能的，并且这些结构中的哪一个应该被AD疗法、实验旨在从总体上理解Aβ组装。初步数据显示， 150个Aβ寡聚体（32个Aβ肽分子）的稳定均质样品，并使用固态核磁共振（NMR）和电子显微镜（EM）。值得注意的是，150 kDa寡聚体这种结构不同于任何先前理解的Aβ组装，这一观察提供了一个独特的机会，以探测低聚物和原纤维结构如何不同。该项目将追求高分辨率的原子级通过整合固态NMR、冷冻EM和计算建模来表征150 kDa寡聚体。这项工作进一步试图通过测试假设的受150 kDa寡聚体启发的组装途径。拟议的工作将：实现三维图像 150 kDa寡聚体的使用冷冻EM（目的1）;测量互补的原子水平的结构约束，固态NMR（目标2）;和测试机制假设，以产生新的低聚物兼容EM和 NMR工作流程（目标3）。了解Aβ可能的寡聚体结构（以及如何分离特定的结构）对于开发新的阿尔茨海默氏症疗法，实施早期检测策略，设计疾病模型的机制研究。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A common pathway for detergent-assisted oligomerization of Aβ42.

DOI：
10.1038/s42003-023-05556-w
发表时间：
2023-11-21
期刊：
COMMUNICATIONS BIOLOGY
影响因子：
5.9
作者：
Muhammedkutty, Fidha Nazreen Kunnath;Prasad, Ramesh;Gao, Yuan;Sudarshan, Tarunya Rao;Robang, Alicia S;Watzlawik, Jens O;Rosenberry, Terrone L;Paravastu, Anant K;Zhou, Huan-Xiang
通讯作者：
Zhou, Huan-Xiang