The structural basis of apoE4's role in Alzheimer's Disease

apoE4 在阿尔茨海默病中作用的结构基础

• 批准号: 8068746
• 负责人: JOHN Carl VOSS
• 金额: $ 24.1万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068746
• 关键词: Accounting; Address; Alleles; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid Fibrils; Apolipoprotein E; Appearance; Attention; Binding; Brain; Charge; Chemicals; Confusion; Data; Electron Microscopy; Electrons; Equilibrium; Event; Figs - dietary; Fluorescence Spectroscopy; Frequencies; Gene Frequency; Heterogeneity; Human; In Vitro; Maintenance; Maps; Methods; Molecular; Molecular Chaperones; Molecular Conformation; Nerve Degeneration; Neurons; Outcome; Peptides; Play; Population; Positioning Attribute; Process; Property; Protein Conformation; Protein Isoforms; Proteins; Reporting; Research Personnel; Risk Factors; Role; Sampling; Screening procedure; Side; Site; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spin Labels; Structure; Surface Plasmon Resonance; System; Technology; Testing; Toxic effect; Translating; Work; apolipoprotein E-3; apolipoprotein E-4; base; conformational conversion; design; drug candidate; experience; intermolecular interaction; lipid metabolism; lipid transport; programs; spatial relationship; structural biology; tool

DESCRIPTION (provided by applicant): Apolipoprotein E (apoE) is a 299 amino acid (~34 kD) protein that plays a central role in lipid transport and metabolism. Unlike apoE3 and apoE2, apoE4 is an established risk factor for Alzheimer's disease (AD). However, the molecular basis of these isoform-specific effects is largely unknown and, most importantly, has not been explored systematically in terms of structure and function. Most attention has been focused on the influence of apoE on A¿ peptide processing in the brain. Specific Aims. Aim 1: Identify the initiation of beta structure in apoE4. Aim 2: Characterize the interaction of apoE isoforms with the A¿ peptide. These aims will illuminate the most important details needed for achieving a mechanistic understanding of how apoE4 participates in AD and neurodegeneration in general. Guided by our (including collaborators) expertise on the functional system, we have the experience and technology to uniquely contribute to this problem by applying the structural biology tools most likely to uncover the basis for the apoE isoform effect in AD. These tools include fluorescence spectroscopy, electron microscopy, surface plasmon resonance, and FTIR spectroscopy, though our primary method will utilize electron paramagnetic (EPR) spectroscopy of site-directed spin labels. Significance. Because of the ability of EPR to report on local structure and spatial relationships from the sample in solution, this work may translate into an effective tool for drug candidate screening. Possibilities include use of spin-labeled side chains to evaluate beta-strand blockers designed to target an identified domain or charged chemical chaperones that stabilize a labile region within apoE. Since apoE3 may also experience destabilized conformations, though at a much lower frequency, such treatments may be helpful in slowing the progression of AD in E3 carriers as well.

描述（由申请人提供）：载脂蛋白 E (apoE) 是一种 299 个氨基酸 (~34 kD) 的蛋白质，在脂质转运和代谢中发挥核心作用。与 apoE3 和 apoE2 不同，apoE4 是阿尔茨海默病 (AD) 的既定危险因素。然而，这些亚型特异性效应的分子基础在很大程度上是未知的，最重要的是，尚未在结构和功能方面进行系统的探索。大多数注意力都集中在 apoE 对大脑中 A¿ 肽加工的影响上。 具体目标。 目标 1：确定 apoE4 中 β 结构的起始。 目标 2：表征 apoE 同工型与 A¿ 肽的相互作用。 这些目标将阐明实现 apoE4 如何参与 AD 和神经退行性病变的机制理解所需的最重要细节。在我们（包括合作者）功能系统专业知识的指导下，我们拥有经验和技术，通过应用最有可能揭示 AD 中 apoE 同工型效应基础的结构生物学工具，为解决这个问题做出独特的贡献。这些工具包括荧光光谱、电子显微镜、表面等离子体共振和 FTIR 光谱，尽管我们的主要方法将利用定点自旋标签的电子顺磁 (EPR) 光谱。 意义。由于 EPR 能够报告溶液中样品的局部结构和空间关系，这项工作可能会转化为候选药物筛选的有效工具。可能性包括使用自旋标记侧链来评估β链阻断剂，该β链阻断剂旨在靶向已识别的结构域或稳定apoE内不稳定区域的带电化学伴侣。由于 apoE3 也可能经历不稳定的构象，尽管频率要低得多，因此此类治疗也可能有助于减缓 E3 携带者 AD 的进展。

项目成果

The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide.

• DOI: 10.1371/journal.pone.0035443
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Petrlova J;Kálai T;Maezawa I;Altman R;Harishchandra G;Hong HS;Bricarello DA;Parikh AN;Lorigan GA;Jin LW;Hideg K;Voss JC
• 通讯作者: Voss JC

Binding of apolipoprotein E inhibits the oligomer growth of amyloid-β peptide in solution as determined by fluorescence cross-correlation spectroscopy.

载脂蛋白 E 的结合抑制溶液中淀粉样β 肽的低聚物生长，如荧光互相关光谱测定。

• DOI: 10.1074/jbc.m112.411900
• 发表时间: 2013
• 期刊: The Journal of biological chemistry
• 作者: Ly,Sonny;Altman,Robin;Petrlova,Jitka;Lin,Yu;Hilt,Silvia;Huser,Thomas;Laurence,TedA;Voss,JohnC
• 通讯作者: Voss,JohnC