Membrane lipid peroxidation in pathogenesis of Alzheimer’s disease

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， 受到活性氧的攻击，导致脂质过氧化。AD脑中脂质过氧化增加， 被认为在驱动AD的神经变性中起关键作用。然而，补充脂溶性 抗氧化剂在临床试验中只产生混合结果。因此，脂质过氧化在AD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，其可以通过以下方式抑制脂质过氧化： 直接减少膜中的磷脂过氧化氢。因此，Gpx4抑制脂质过氧化 通过一种不同于脂质抗氧化剂的机制。GPX4在减少磷脂过氧化氢中的作用 在细胞如神经元中是至关重要和不可或缺的。Gpx4也是铁凋亡的主要调节因子。 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起着关键作用， 例如在AD中受到严重折磨的前脑神经元。在初步研究中，我们获得的数据表明， AD大脑中存在Gpx4功能障碍，可能导致加重的发病机制， Gpx4功能延缓AD小鼠模型的认知障碍在这个项目中，我们将确定是否 由Gpx4缺乏诱导的膜脂质过氧化增加阐明了疾病的发病机制， 神经变性，并确定Gpx4过表达在延缓认知障碍和 AD小鼠的神经变性。本项目检验的总体假设为： 减轻体内Aβ神经毒性，增强Gpx4功能，抑制膜脂质过氧化 将延缓AD发病。这一假设将通过三个具体目标进行检验。目的1是确定效果 Gpx4缺陷引起的膜脂质过氧化反应在AD发病中的作用。目标2是确定是否 Gpx4过表达可抑制AD小鼠的神经退行性变并改善其认知功能。目标3是 确定通过用病毒载体转导的Gpx4过表达是否可以延缓疾病的进展， 不同疾病阶段的AD小鼠。我们的研究将确立膜脂过氧化在 AD的神经退行性变，并为Gpx4作为AD的靶点的功效提供概念验证证据。 干预以延缓AD的进展。

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.