Membrane-Mediated Toxicity of Beta-Amyloid Oligomers

描述（由申请人提供）：细胞膜是所有高等生命形式的信号传输机制中的核心元件。因此，它被广泛接受，A？寡聚体与膜的相互作用在阿尔茨海默病的发病机制中起重要作用。然而，A的分子理解？迄今为止，AD的神经毒性仍然缺失。通过生物物理实验和理论/模拟的协调使用，该程序项目（M。L“sche，主任）将提供分子尺度的信息A？寡聚体与膜的相互作用，肽聚集态的转化及其对膜纳米结构的影响，以及这些因素对膜嵌入离子通道的影响。该计划包括两个核心和三个研究项目。核心A和B为计划项目的管理提供资源（核心A; M。L“sche，PI）和用于肽合成和寡聚体特异性抗体形式的免疫试剂（核心B：C. G. Glabe，PI）。 研究项目1：A？低聚物与细胞和BLM中电导机制的相互作用（J. E. Hall，PI）。Irvine小组将测量具有明确化学成分的独立膜和细胞膜对A？的生电反应，并将开发相互作用的模型。项目2：A？的结构和功能研究低聚物与合成膜的相互作用（M。L“sche，PI）.稀疏拴系双层脂质膜（stBLMs）被用来表征分子间的相互作用，宪法的变化，和抗体与膜结合的A？（NCNR的中子反射;卡内基梅隆大学CMU的电化学和光学技术的补充）。膜重建协议的stBLMs也将开发和A？将测定膜包埋的KcsA上的寡聚体。项目3：模拟A？低聚物与膜的相互作用（M. P.I.）。粗粒度模拟A？在CMU的低聚物和膜将开发研究肽的结构转化和辅助实验数据解释。合作项目：（1）膜通道生物物理学（J。A。Mindell，PI）。NINDS实验室有一个关于离子通道的积极研究计划，并将提供KcsA膜重建的专业知识。(2)栓系双层膜的电化学光谱（G。Valincius，PI; Institute of Biochemistry，Vilnius，Lithuania）。该集团支持PPG在电化学阻抗谱（EIS）的专业知识，在一个新的领域。

DESCRIPTION (provided by applicant): Cell membranes are central elements in the signal transmission machinery of all higher life forms. It is therefore widely accepted that A? oligomer interactions with membranes play an important role in Alzheimer's pathogenesis. Yet, a molecular understanding of A? neurotoxicity in AD is still missing to date. By the concerted use of biophysical experimentation and theory/simulation, this program project (M. L"sche, Director) will provide molecular-scale information on A? oligomer interaction with membranes, transformations of peptide aggregate states and their impact on membrane nanostructure, and the effect of these factors on membrane embedded ion channels. The program consists of two Cores and three Research Projects. Cores A and B provides resources for the administration of the Program Project (Core A; M. L"sche, PI) and for peptide synthesis and immuno-reagents in the form of oligomer-specific antibodies (Core B: C. G. Glabe, PI). Research Project 1: Electrophysiology of A? Oligomer Interaction with Conductance Mechanisms in Cells and BLMs (J. E. Hall, PI). The Irvine group will measure electrogenic responses of free-standing membranes with well-defined chemical compositions and of cell membranes to A?, and will develop models of the interactions. Project 2: Structural and Functional Investigations of A? Oligomer Interaction with Synthetic Membranes (M. L"sche, PI). Sparsely tethered bilayer lipid membranes (stBLMs) are used to characterize molecular interactions, constitutional changes, and antibody interaction with membrane-bound A? (neutron reflection at NCNR; complementing electrochemical and optical techniques at Carnegie Mellon, CMU). Membrane reconstitution protocols for stBLMs will also be developed and the impact of A? oligomers on membrane-embedded KcsA will be determined. Project 3: Simulation of A? Oligomer Interaction with Membranes (M. Deserno, PI). Coarse-grained simulations of A? oligomers and membranes at CMU will be developed to investigate structural transformations of peptide and aid experimental data interpretation. Collaborations: (1) Membrane Channel Biophysics (J. A. Mindell, PI). The NINDS lab has an active research program on ion channels and will provide know-how on KcsA membrane reconstitution. (2) Electrochemical Spectroscopy of Tethered Bilayers (G. Valincius, PI; Institute of Biochemistry, Vilnius, Lithuania). The group supports the PPG with their expertise in electrochemical impedance spectroscopy (EIS) in a subcontract.