Structure/Function Analysis of A-beta Fibril Assembly

描述(申请人提供)：淀粉样纤维和其他有序的 阿尔茨海默氏症斑块多肽A-β的聚集产物 与遗传、病理和细胞培养研究有关，在 阿尔茨海默病的发展。针对增长或 这些聚集体的毒性在形式上是可能的，但在技术上是困难的 部分原因是我们对原纤维结构和原纤维集合体都一无所知 路径和能量学。在这项拨款申请中，我们建议实施新的 获取结构和组装信息的战略，这将 例如，对原纤维抑制剂的设计和测试作出贡献 队形。我们将利用扫描诱变技术连接到一些体外 分析关键氨基酸残基在纤维生长中的作用 A-β在纤维形成和稳定性中的位置。我们将使用Surface 等离子体共振(SPR)研究纤维组装动力学和 用野生型和突变型A-β序列进行拆解。

DESCRIPTION (Provided by applicant): Amyloid fibrils and other ordered aggregation products of the Alzheimer's plaque peptide A-beta have been implicated by genetic, pathological, and cell culture studies to have a role in the development of Alzheimer's disease. Strategies targeting the growth or toxicity of these aggregates are formally possible but technically difficult owing in part to our ignorance of both fibril structure and of fibril assembly pathways and energetics. In this grant application we propose to implement new strategies to obtain information on structure and assembly, which will contribute, for example, to both the design and testing of inhibitors of fibril formation. We will utilize scanning mutagenesis linked to a number of in vitro assays for fibril growth to dissect the roles of key amino acid residue positions of A-beta in fibril formation and stability. We will use surface plasmon resonance (SPR) to study details of the kinetics of fibril assembly and disassembly with both wild type and mutant A-beta sequences.