Ion Mobility Spectrometry Reveals the Mechanism of Amyloid Formation of Aβ(25-35) and Its Modulation by Inhibitors at the Molecular Level: Epigallocatechin Gallate and Scyllo-inositol
Ion Mobility Spectrometry Reveals the Mechanism of Amyloid Formation of Aβ(25-35) and Its Modulation by Inhibitors at the Molecular Level: Epigallocatechin Gallate and Scyllo-inositol
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DOI：
10.1021/ja406197f
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发表时间：
2013-11-13
影响因子：
15
通讯作者：
Bowers, Michael T.
中科院分区：
文献类型：
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作者：
Bleiholder, Christian;Do, Thanh D.;Bowers, Michael T.
淀粉样蛋白级联导致肽- β片原纤维和斑块是许多重要疾病的核心。最近，这些级联的中间组件被确定为与细胞机制相互作用的有毒物质。从天然非结构化组装到β -片低聚物到疾病的转变之间的关系对于理解疾病的发生和治疗剂的开发是重要的。由于传统技术只能测量整体平均低聚物性质，因此对这一早期低聚物区域的研究在很大程度上是不成功的。在这里，离子迁移方法被用来推断两种淀粉样蛋白抑制剂（表没食子儿茶素没食子酸酯和scyllo-肌醇）对淀粉样蛋白片段A β(25-35)中肽自组装途径的调节，这两种淀粉样蛋白抑制剂目前正在阿尔茨海默病的临床试验中。我们提供的证据表明，从β -延伸低聚物转化为β -低聚物构象的开始抑制β -延伸低聚物对于有效衰减β -结构淀粉样蛋白低聚物物种是必不可少的，通常与低聚物毒性有关。此外，我们证明了离子迁移谱-质谱法可以通过提供对淀粉样蛋白形成过程及其由小分子组装调节剂调节的分子水平的洞察来指导治疗剂的开发和药物评估。
Amyloid cascades leading to peptide beta-sheet fibrils and plaques are central to many important diseases. Recently, intermediate assemblies of these cascades were identified as the toxic agents that interact with the cellular machinery. The relationship between the transformation from natively unstructured assembly to the beta-sheet oligomers to disease is important in understanding disease onset and the development of therapeutic agents. Research on this early oligomeric region has largely been unsuccessful since traditional techniques measure only ensemble average oligomer properties. Here, ion mobility methods are utilized to deduce the modulation of peptide self-assembly pathways in the amyloid-beta protein fragment A beta(25-35) by two amyloid inhibitors (epigallocatechin gallate and scyllo-inositol) that are currently in clinical trials for Alzheimer's Disease. We provide evidence that suppression of beta-extended oligomers from the onset of the conversion into beta-oligomer conformations is essential for effective attenuation of beta-structured amyloid oligomeric species often associated with oligomer toxicity. Furthermore, we demonstrate the ease with which ion mobility spectrometry mass spectrometry can guide the development of therapeutic agents and drug evaluation by providing molecular level insight into the amyloid formation process and its modulation by small molecule assembly modulators.