Combining electron and nuclear magnetic resonance to track Alzheimer's amyloid-beta oligomer-to-fibril conversion

结合电子和核磁共振来追踪阿尔茨海默病β淀粉样蛋白寡聚物到原纤维的转化

基本信息

批准号：
10662904
负责人：
Zhefeng Guo
金额：
$ 23.88万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662904
关键词：
Adopted Aliquot Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Amyloid Fibrils Amyloid beta-42 Amyloid beta-Protein Antibodies Binding Brain Calcium Cell Nucleus Dependence Detergents Dissociation Electron Spin Resonance Spectroscopy Electrons Event Fluorescence Goals Hippocampus Impairment In Vitro Incubated Isotopes Kinetics Label Laboratories Lead Lipid Bilayers Lipids Liposomes Long-Term Potentiation Measurement Measures Mitochondria Molecular Conformation Monitor Movement Neurons Nuclear Magnetic Resonance Pathogenesis Pathologic Pathologic Processes Phosphorylcholine Play Positioning Attribute Procedures Process Proteins Public Health Ramp Resolution Role Sampling Signal Transduction Slice Stains Structure Synapses System Temperature Testing Therapeutic Intervention Time Transgenic Mice Transmission Electron Microscopy Vesicle Water Width abeta accumulation abeta oligomer beta pleated sheet conformational conversion design experimental study insight interest monomer presynaptic real time monitoring solid state nuclear magnetic resonance success tau Proteins

项目摘要

Project Summary/Abstract Aggregation of Aβ protein plays a central role in the pathogenesis of Alzheimer's disease. Aβ aggregation leads to the formation of soluble oligomers and insoluble fibrils. While amyloid fibrils are the main component of parenchymal plaques in Alzheimer's disease brains, the Aβ oligomers have been widely regarded as more toxic and more pathologically relevant. There is strong evidence supporting that at least some types of Aβ oligomers can undergo a conformational conversion to form fibrils. It is yet poorly understood how the oligomers could re-arrange their structures to form fibrils. In this proposed project, we will use a combination of electron and nuclear magnetic resonance to monitor structural changes during Aβ42 oligomer-to-fibril conversion. The Aβ42 oligomers will be prepared in the presence of low concentrations of detergent. These Aβ42 oligomers represent a type of stable oligomers, which convert to fibrils only in the presence of lipid vesicles. The oligomer-to-fibril conversion will be followed by performing EPR and NMR experiments at different time points. This study will provide insights into whether oligomers dissociate to monomers, which then nucleate to form fibril nuclei, or oligomers transition to the structure of fibril nuclei without dissociation. We will not only delineate the mechanism of Aβ aggregation, but also shed light on how to modulate this process as a way of therapeutic intervention.

项目概要/摘要 Aβ 蛋白的聚集在阿尔茨海默病的发病机制中起着核心作用。导致可溶性低聚物和不溶性原纤维的形成，而淀粉样原纤维是主要成分。阿尔茨海默病大脑中的实质斑块中，Aβ寡聚物被广泛认为是更有效的有强有力的证据支持至少某些类型的 Aβ 具有毒性且更具病理相关性。低聚物可以进行构象转变以形成原纤维，但人们对如何形成原纤维仍知之甚少。低聚物可以重新排列其结构以形成原纤维。在这个拟议的项目中，我们将使用以下物质的组合。电子和核磁共振监测 Aβ42 寡聚物到原纤维过程中的结构变化 Aβ42 寡聚物将在低浓度去污剂存在下制备。 Aβ42 寡聚体代表一种稳定的寡聚体，仅在脂质存在的情况下才会转化为原纤维低聚物到原纤维的转化将在以下温度进行 EPR 和 NMR 实验。这项研究将提供有关低聚物是否解离为单体的见解。然后成核形成原纤维核，或低聚物转变为原纤维核结构而不解离。不仅会描述 Aβ 聚集的机制，还会阐明如何调节这一过程作为治疗干预的一种方式。