Structural basis of biological active β-amyloid conformers

以淀粉样纤维形式沉积的β-淀粉样多肽是神经退行性疾病的一个标志，如脑淀粉样血管病(CAA)和阿尔茨海默病(AD)。这些事件的基础是一种分子自组装反应，这种反应可以由预先形成的淀粉样纤维在体外播种，也可以通过在阿尔茨海默病小鼠模型中脑内注射含有Abeta的脑提取物来进行。越来越多的证据表明，这种效应是由Abeta纤维引起的。Abeta纤维也可能在CAA中发挥致病作用，尽管AD的神经退化可能更多地依赖于中间状态的毒性作用。在体外，对于不同的Abeta纤维或中间体制剂，已经获得了相互矛盾的结构模型，而在疾病患者体内形成的Abeta纤维的结构尚不清楚。在这个项目中，我们将从患病的人体组织中提纯Abeta纤维，使其可用于高端生物物理方法，特别是电子显微镜的直接结构分析。预期的结果可能对了解神经退行性疾病的传播具有重要意义。

The deposition of beta-amyloid (Abeta) peptide as amyloid fibrils is ahallmark of neurodegenerative conditions, such as cerebral amyloidangiopathy (CAA) and Alzheimer´s disease (AD). Underlying theseevents is a molecular self-assembly reaction that can be seeded invitro by preformed amyloid fibrils and in vivo by intracerebral injectionof Abeta-containing brain extracts into Alzheimer mouse models.Increasing evidence shows that this effect is provoked by Abeta fibril.Abeta fibrils may also play a pathogenic role in CAA, althoughneurodegeneration in AD may rather depend on the toxic effect ofintermediate states. Conflicting structural models have been obtainedfor different preparations of Abeta fibrils or intermediates in vitro, whilethe structure of Abeta fibrils formed inside a diseased patient remainunclear. In this project we will purify Abeta fibrils from diseased humantissue to make it available for direct structural analysis with high end biophysical methods, including in particular electron microscopy.Expected results may be important for understandning the spreadingof neurodegenerative diseases.