Membrane lipid peroxidation in pathogenesis of Alzheimer’s disease

膜脂质过氧化在阿尔茨海默病发病机制中的作用

• 批准号: 10615076
• 负责人: QITAO RAN
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615076
• 关键词: Ablation; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; American; Amyloid beta-Protein; Antioxidants; Automobile Driving; Autopsy; Biological; Cell Death; Cells; Central Nervous System; Clinical Trials; Cognition; Data; Dependovirus; Disease; Disease Progression; Ensure; Free Radicals; Functional disorder; Hydrogen Peroxide; Impaired cognition; Intervention; Iron; Knockout Mice; Lipid Peroxidation; Lipids; Membrane; Membrane Lipids; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Phase; Phenotype; Phospholipids; Play; Polyunsaturated Fatty Acids; Predisposition; Prosencephalon; Reaction; Reactive Oxygen Species; Role; Series; Specimen; Supplementation; System; Testing; Transgenic Mice; Transgenic Organisms; Viral Vector; Virus; Vitamin E; abeta accumulation; cell injury; conditional knockout; efficacious treatment; efficacy evaluation; gene therapy; glutathione peroxidase; improved; in vivo; interest; mature animal; mouse model; neuronal survival; neurotoxicity; overexpression; oxidation; therapeutic evaluation; therapeutic target

ABSTRACT Alzheimer's disease (AD) is the most common neurodegenerative disease affecting millions of Americans. Neurons have a large amount of polyunsaturated fatty acids in membrane phospholipids that are vulnerable to attack by reactive oxygen species to result in lipid peroxidation. Lipid peroxidation is increased in AD brains and is believed to play a key role in driving neurodegeneration of AD. However, supplementation of lipid soluble antioxidants yields only mixed results in clinical trials. So the importance of lipid peroxidation in AD remains unproven. Glutathione peroxidase 4 (Gpx4) is a glutathione peroxidase that can suppress lipid peroxidation by directly reducing phospholipid hydroperoxides in membranes. Therefore, Gpx4 suppresses lipid peroxidation through a mechanism distinct from that of lipid antioxidants. Gpx4's role in reducing phospholipid hydroperoxides in cells such as neurons is critical and indispensable. Gpx4 also serves as the master regulator of ferroptosis. We have demonstrated that Gpx4 plays a critical role in ensuring heath and survival of neurons in adult animals, such as forebrain neurons that are severely afflicted in AD. In preliminary studies, we obtained data indicating that there is a Gpx4 dysfunction in AD brains that could lead to exacerbated pathogenesis and that enhanced Gpx4 function retards cognitive impairment of AD mouse models. In this project, we will determine whether increased membrane lipid peroxidation induced by Gpx4 deficiency aggravates disease pathogenesis such as neurodegeneration, and determine the efficacy of Gpx4 overexpression in retarding cognitive impairment and neurodegeneration in AD mice. The overall hypothesis tested in this project is: Membrane lipid peroxidation aggravates Aβ neurotoxicity in vivo, and augmentation of Gpx4 function to suppress membrane lipid peroxidation will retard AD pathogenesis. The hypothesis will be tested by three specific aims. Aim 1 is to determine the effect of membrane lipid peroxidation induced by Gpx4 deficiency on AD pathogenesis. Aim 2 is to determine whether overexpression of Gpx4 can suppress neurodegeneration and improve cognition in AD mice. Aim 3 is to determine whether Gpx4 overexpression via transduction with viral vector can retard progression of disease in AD mice at different disease stages. Our study will establish the importance of membrane lipid peroxidation in neurodegeneration of AD and provide proof-of-concept evidence for the efficacy of Gpx4 as a target of intervention to retard progression of AD.

摘要 阿尔茨海默病(AD)是影响数百万美国人的最常见的神经退行性疾病。 神经元在膜磷脂中含有大量的多不饱和脂肪酸，容易受到 受活性氧的攻击，导致脂质过氧化。阿尔茨海默病患者大脑中的脂质过氧化反应增加 被认为在阿尔茨海默病的神经退行性变中起着关键作用。然而，补充脂溶的 抗氧化剂在临床试验中的效果好坏参半。因此脂质过氧化在阿尔茨海默病中的重要性仍然存在 未经证实。谷胱甘肽过氧化物酶4(Gpx4)是一种谷胱甘肽过氧化物酶，可通过以下途径抑制脂质过氧化 直接还原膜中的磷脂过氧化氢。因此，Gpx4抑制脂质过氧化 通过一种与脂类抗氧化剂不同的机制。Gpx4‘S在还原磷脂过氧化氢中的作用 在神经元等细胞中是至关重要的，也是不可或缺的。Gpx4也是铁性下垂的主要调节因子。 我们已经证明，Gpx4在确保成年动物神经元的健康和存活方面发挥着关键作用， 例如，在阿尔茨海默病中严重受影响的前脑神经元。在初步研究中，我们获得的数据表明 阿尔茨海默病患者大脑中存在Gpx4功能障碍，这可能导致发病机制的恶化和增强 Gpx4功能延缓AD模型小鼠的认知功能障碍。在这个项目中，我们将确定是否 Gpx4缺乏引起的膜脂质过氧化增加加剧了疾病的发病机制，如 神经退行性变，并确定Gpx4过表达在延缓认知功能障碍和 阿尔茨海默病小鼠的神经变性。这个项目检验的总体假设是：膜脂过氧化 体内加重β神经毒性和增强Gpx4功能以抑制膜脂过氧化 会延缓AD的发病机制。这一假设将通过三个具体目标进行检验。目标1是确定影响 Gpx4缺乏引起的膜脂过氧化在AD发病机制中的作用。目标2是确定是否 Gpx4过表达可抑制AD小鼠神经退行性变，改善认知功能。目标3是 确定通过病毒载体转导Gpx4过表达是否可以延缓疾病的进展 AD小鼠处于不同疾病阶段。我们的研究将确定膜脂质过氧化的重要性。 阿尔茨海默病的神经退行性变并为Gpx4作为靶点的疗效提供概念验证证据 干预以延缓AD的进展。