Membrane-Mediated Toxicity of Beta-Amyloid Oligomers

描述(申请人提供)：细胞膜是所有高等生命形式的信号传输机制的中心元素。因此，人们普遍认为A？低聚物与膜的相互作用在阿尔茨海默病的发病机制中起着重要作用。然而，对A的分子理解呢？到目前为止，阿尔茨海默病的神经毒性仍不清楚。通过生物物理实验和理论/模拟的协同使用，本计划项目(M.L主任)将提供A低聚物与膜相互作用的分子尺度信息，多肽聚集态的变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。该计划由两个核心和三个研究项目组成。核心A和B为计划项目的管理(核心A；M·L“战略，PI)和以寡聚体特异性抗体形式的多肽合成和免疫试剂(核心B：C.G.Glabe，PI)提供资源。 研究项目1：A？低聚物在细胞和BLM中与电导机制的相互作用(J.E.Hall，PI)。欧文小组将测量具有明确化学成分的独立膜和细胞膜对A？的电响应，并将开发相互作用的模型。项目2：A？齐聚物与合成膜的相互作用(M.L)。稀疏双分子层类脂膜(StBLMs)用于表征分子相互作用、组成变化以及抗体与膜结合的A？(NCNR的中子反射；对卡内基梅隆大学的电化学和光学技术的补充)。还将开发用于stBLMS的膜重建协议，以及A？膜包埋KCSA上的低聚物将被确定。项目3：模拟A？齐聚物与膜的相互作用(M。Disno，PI)。粗粒度模拟A？将在CMU开发低聚物和膜，以研究多肽的结构转换并帮助解释实验数据。合作：(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活跃研究计划，并将提供KCSA膜重建方面的技术诀窍。(2)系留双分子层的电化学光谱(G.Valincus，PI；立陶宛维尔纽斯生物化学研究所)。该集团在分包合同中以其在电化学阻抗谱(EIS)方面的专业知识为PPG提供支持。 对各个组件的审查 核心A--行政核心；马蒂亚斯·L博士，核心领导(CL) 描述(由申请人提供)：该行政核心在所有相关行政问题上为计划项目提供协助和资源。

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. REVIEW OF INDIVIDUAL COMPONENTS CORE A - ADMINISTRATIVE CORE; Dr. Mathias L"sche, Core Leader (CL) DESCRIPTION (provided by applicant): This administrative core provides assistance and resources to the Program Projects in all relevant administrative issues.