Kinetic and thermodynamic analysis of the molecular interaction on amyloid fibril formation

淀粉样原纤维形成分子相互作用的动力学和热力学分析

基本信息

批准号：
18570149
负责人：
HASEGAWA Kazuhiro
金额：
$ 2.63万
依托单位：
University of Fukui
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18570149/
关键词：
Biophysics Biological molecules Amyloid fibril Alzheimaer's disease Dialysis-related amyloidosis

项目摘要

Amyloid is extracellular deposit of insoluble fibrillar aggregate of proteins those are normally soluble in their native conformation, resulting in the impairment of tissue structure and function. We have established several amyloid fibril formation systems in vitro, including β-amyloid of Alzheimer's disease (Aβ) and β2-microglobulin (β2-m) amyloid (Aβ2M) of dialysis-related amyloidosis. Using these systems, important roles of various biological molecules or compounds on the formation and dissociation of amyloid fibrils were discovered. To model the amyloid fibril formation in vivo by in vitro experimental system or numerical model, we selected several phases of fibril formation or dissociation, and clarified their mechanism by biophysical, kinetic and thermodynamic analyses.1. To understand the molecular pathogenesis of Aβ2M amyloidosis, the biological molecules that induce amyloid fibril formation by affecting the conformation and stability of β2-m and amyloid fibrils need to be ide … More ntified. We showed that anionic amphipathic compounds including non-esterified fatty acids (NEFAs) and some lysophospholipids induce the fibril extension at a neutral pH. Furthermore, hemodialysis patients had significantly higher plasma concentrations of lysophospholipids than healthy subjects. These results suggest possible role of lysophospholipids and NEFAs in the development of Aβ2M amyloidosis.2. Using spectrophotometry, spectrofluorometry and surface plasmon resonance, we investigated the anti-amyloidogenic effects of five flavonoids on β-amyloid fibril (fAβ) in vitro. The results suggest that flavonoids, especially myricetin exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fAβ, rather than to Aβ monomers.3. We developed a high-throughput screening system for the nucleation of Aβ2M and Aβ amyloid fibril using thioflavin T fluorescence spectroscopy. Using this system, effect of various biological molecules including proteoglycans, glycosaminoglycans, were investigated. As the conclusion of this study, the remarkable advance in the clarification of the mechanism of Aβ2M and Aβ amyloid fibril formation were obtained. Less

淀粉样蛋白是蛋白质的布里尔骨骼外骨，通常在其本地构象中溶于其组织和功能。（Aβ2M）透析相关的囊肿或化合物在淀粉样蛋白纤维的形成和分离中被发现，以模拟体外实验系统或数值模型的淀粉样蛋白形成.1。中性pH值。尤其是单元素在体外发挥抗淀粉样蛋白作用。在阐明Aβ2M和Aβ淀粉样蛋白的机理方面进行了研究