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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.

项目概要在阿尔茨海默病 (AD) 研究中，β 淀粉样蛋白 (Aβ) 的寡聚体组装成为焦点肽（一种小蛋白质）。寡聚物是由 50 个或更少的肽聚集而成的小纳米粒子分子。肽聚集最容易产生淀粉样原纤维，而是什么阻止了某些淀粉样原纤维的形成仍是一个谜。低聚物进一步聚集成原纤维。即使在寡聚体和纤维状聚集体类别中，肽已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且结构均质的样品以获得高分辨率信息。为了阐明什么低聚物结构是可能的，AD 疗法、实验应针对这些结构中的哪一个旨在一般性地了解 Aβ 组装。初步数据表明，可以生产 150 个 Aβ 寡聚物（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 寡聚体结构与之前理解的任何 Aβ 组装不同，这一观察提供了一个独特的机会探究低聚物和原纤维结构有何不同。该项目将追求高分辨率原子级通过集成固态 NMR、冷冻电镜和计算模型来表征 150 kDa 低聚物。这项工作进一步试图通过测试假设来概括对 Aβ 组装机制的理解受 150 kDa 寡聚物启发的组装途径。拟议的工作将：实现 3 维图像使用冷冻电镜分析 150 kDa 寡聚物（目标 1）；测量互补的原子级结构约束固态核磁共振（目标 2）；并测试机制假设以生产与 EM 和兼容的新低聚物 NMR 工作流程（目标 3）。了解 Aβ 可能具有哪些寡聚体结构（以及如何分离特定的结构）对于开发新的阿尔茨海默病疗法、实施早期检测策略至关重要，并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