Structure/Function Analysis of A-beta Fibril Assembly

描述（由申请人提供）：淀粉样纤维和其他有序 阿尔茨海默氏症斑块肽A-β的聚集产物已经被 遗传学、病理学和细胞培养研究表明， 老年痴呆症的发展针对增长或 这些聚集体的毒性形式上是可能的，但技术上是困难的 部分原因是我们对原纤维结构和原纤维组装都不了解 路径和能量学。在这份拨款申请中，我们建议实施新的 获得结构和组装信息的战略， 例如，有助于原纤维抑制剂的设计和测试， 阵我们将利用扫描诱变连接到一些体外 原纤维生长的测定以剖析关键氨基酸残基的作用 A-β在原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）来研究原纤维组装的动力学细节， 用野生型和突变型A-β序列进行的解装配。

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.