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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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.

抽象的阿尔茨海默氏病（AD）是数百万美国人的最常见神经退行性疾病。神经元在容易受到伤害的膜磷脂中具有大量的多突化脂肪酸。活性氧的攻击会导致脂质过氧化。但是，在驱动AD的神经变性方面起着关键作用。抗氧化剂仅在临床试验中产生混合的结果。未经证实因此，直接减少膜中的磷脂氢过氧化物。通过与脂质抗氧化剂不同的机制。在诸如神经元之类的细胞中，至关重要且必不可少。我们已经证明，GPX4在确保和在安德曼的神经元中的生存中起着至关重要的作用，例如，在AD中折磨的前脑神经元。 AD大脑中有GPX4功能障碍，可能导致加剧的发病机理，并增强 GPX4函数延迟了AD鼠标模型的认知障碍。 GPX4诱导的膜脂质过氧化增加增加了疾病发病机理，例如神经变性，并确定GPX4过表达在延迟认知障碍和 AD小鼠的神经变性。在体内加重Aβ神经毒性，并增强GPX4功能以抑制膜脂质过氧化将通过三个特定目标来测试AD的发病机理。由GPX4缺乏引起的AD发病机理引起的膜脂质过氧化。 GPX4的过表达可以抑制AD小鼠的神经变性并改善认知。确定通过用载体载体转导的GPX4过表达是否会阻碍疾病进展在不同疾病阶段的AD小鼠将确定膜脂质过氧化的重要性 AD的神经变性为GPX4作为目标的有效性提供了概念验证证据干预以延迟AD的进度。