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信号传输机制的中心元素。因此，人们普遍认为A？寡聚物与细胞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，对a的分子理解？阿尔茨海默病的神经毒性至今仍不清楚。通过生物物理实验和理论/模拟的协同使用，该项目（M. L"sche，主任）将提供A？低聚物与膜的相互作用，肽聚集态的转变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。该项目由两个核心项目和三个研究项目组成。核心A和B为项目管理提供资源（核心A； M. L . sche， PI），以及肽合成和寡聚特异性抗体形式的免疫试剂（核心B: C. G. Glabe， PI）。

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.