Structural Studies of Alzheimer's beta-Amyloid Fibrils

2013财年在以下方面取得了进展： 源自脑组织的淀粉样原纤维结构：我们发表了第一个基于实验的、详细的β-淀粉样原纤维分子结构模型，该模型实际上是在阿尔茨海默病(AD)患者的脑组织中形成的。同一篇文章还包括第二个患者的固态核磁共振和电子显微镜数据，显示两个不同的患者可以在他们的大脑中形成结构不同的β-淀粉样纤维(尽管给定患者的结构是高度均匀的)。这两名患者的临床病史不同，第一名患者被初步诊断为路易体痴呆，第二名患者被初步诊断为阿尔茨海默病。 现在，我们与伦敦大学学院的John Colinger教授合作，从AD患者尸检的30个脑组织样本中获得了固态核磁共振和电子显微镜数据，这些样本来自三种类型(典型的长病史、后皮质萎缩、短病程)。使用我们发表的淀粉样蛋白提取和播种方案，用40-残基和42-残基的β-淀粉样多肽制备了同位素标记的纤维。固态核磁共振数据表明，大多数AD患者在他们的大脑中发展了相同的40个残基的纤维结构，但短期患者可以发展不同的和更不同的结构。42-残基纤维的结果仍在分析中。 这些实验的目的是确定β-淀粉样蛋白纤维的结构变化是否与阿尔茨海默病的发展相关。如果这种相关性被发现是显著的，那么开发区分不同纤维结构的成像剂可能变得重要，并可能开发具有结构特异性的β-淀粉样蛋白聚集抑制剂。

Progress in FY2013 has been in the following areas: AMYLOID FIBRIL STRUCTURES DERIVED FROM BRAIN TISSUE: We have published the first experimentally-based, detailed molecular structural model for beta-amyloid fibrils that actually developed in the brain tissue of an Alzheimer's disease (AD) patient. The same publication included solid state NMR and electron microscopy data for a second patient, showing that two different patients can develop structurally distinct beta-amyloid fibrils in their brains (although the structure within a given patient was highly homogeneous). The two patients had different clinical histories, with the first patient receiving an initial diagnosis of Lewy body dementia and the second patient receiving an initial diagnosis of AD. In collaboration with Prof. John Collinge of University College London, we have now obtained solid state NMR and electron microscopy data for fibrils derived from 30 brain tissue samples from autopsies of AD patients in three categories (typical long history, posterior cortical atrophy, short duration). Using our published amyloid extraction and seeding protocols, isotopically labeled fibrils were prepared using both 40-residue and 42-residue beta-amyloid peptides. The solid state NMR data suggest that most AD patients develop the same predominant 40-residue fibril structure in their brains, but that short duration patients can develop different and more heterogeneous structures. Results for 42-residue fibrils are still under analysis. These experiments are aimed at determining whether structural variations in beta-amyloid fibrils correlate with variations in AD development. If such correlations are found to be significant, then it may become important to develop imaging agents that distinguish among different fibril structures, and possibly to develop beta-amyloid aggregation inhibitors that have structural specificity.