AB MONOMER STRUCTURE AND ASSEMBLY

本研究的目的是在分子水平上了解Abeta蛋白的折叠和组装 异形。最近的研究结果表明，小的，可溶性的Abeta寡聚体负责启动一个新的细胞周期。 导致阿尔茨海默病（AD）的病理级联反应。Abeta 42被证明是主要的 尽管Abeta 40的丰度是神经毒性剂的近10倍。单点氨基酸取代 在A β 42的第22和23位的突变导致了多种家族性AD。我们假设Abeta 单体和小寡聚体是重要的治疗靶点， 折叠和组装的机制是关键的研究目标。在这里，我们建议首先申请 随着时间的推移，离子迁移谱与质谱联用（IMS-MS）的强大方法， Abeta折叠和组装的问题。这些方法提供了单体和低聚物的精确测量 横截面和低聚物尺寸分布。当与高级分子动力学建模相结合时， 获得具有原子细节的单体结构。该方法是超灵敏的，常规工作与 这些方法可以很容易地扩展到其他神经系统疾病， ALS和帕金森病与AD共享错误折叠/聚集基序。 本研究的具体目的是（1）结构表征Abeta单体，并确定如何 这些结构随着单个氨基酸取代、氧化或其它简单的序列修饰而改变， (2)在结构上表征Abeta单体片段，并确定这些结构如何随 序列长度、单氨基酸取代或其它修饰，和（3）测量寡聚体大小 A β和A β 40的修饰形式的组装早期阶段的分布和寡聚体结构， Abeta42.

The objective of this research is to understand, on a molecular level, the folding and assembly of Abeta-protein alloforms. Recent results indicate small, soluble oligomers of Abeta are responsible for initiating a pathological cascade resulting in Alzheimer's disease (AD). Abeta42 has been shown to be the primary neurotoxic agent even though Abeta40 is nearly 10 times more abundant. Single-point amino-acid substitutions at positions 22 and 23 in Abeta42 account for a variety of familial forms of AD. It is our hypothesis that Abeta monomers and small oligomers are important therapeutic targets and characterization of their structure and mechanisms of folding and assembly are critical research objectives. Here we propose to apply, for the first time, the powerful methods of ion mobility spectrometry coupled with mass spectrometry (IMS-MS) to the problem of Abeta folding and assembly. These methods provide accurate measures of monomer and oligomer cross sections and oligomer-size distributions. When coupled with high-level molecular dynamics modeling, monomeric structure with atomic detail is obtained. The method is ultrasensitive, routinely working with picomoles of sample or less. These methods can be readily extended to other neurological diseases like ALS and Parkinson's disease that share the misfolding/aggregation motif with AD. The specific aims of this research are (1) to structurally characterize Abeta monomers and to determine how these structures change with single-amino-acid substitution, oxidation or other simple sequence modification, (2) to structurally characterize Abeta monomer fragments and determine how these structures change with sequence length, single-amino-acid substitutions or other modifications, and (3) to measure oligomer-size distributions and oligomer structures for the early stages of assembly in Abeta and modified forms of Abeta40 and Abeta42.