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

• 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
• 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' s Disease; Alzheimer' s disease therapeutic; Alzheimer' 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

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.

项目总结

项目成果

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