Peroxiredoxin 6 and Alzheimer's

过氧化还原蛋白 6 和阿尔茨海默病

• 批准号: 9303688
• 负责人: WILLIAM C. ORR
• 金额: $ 43.15万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303688
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Antioxidants; Arachidonic Acids; Attention; Chronic; Development; Disease; Disease Progression; Drosophila genus; Engineering; Genes; Human; In Situ; Inflammation; Inflammatory; Intention; Intervention; Lead; Longevity; Mammals; Modeling; Molecular Profiling; Mus; Mutagenesis; Mutation; Neurofibrillary Tangles; Neurons; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathology; Patients; Peroxidases; Phenotype; Phospholipase; Physical activity; Positioning Attribute; Protein Isoforms; Reaction; Research; Role; Scheme; Senile Plaques; Series; Severities; Sulfhydryl Compounds; System; Testing; Tissues; Transgenes; Transgenic Organisms; Translational Research; Variant; amyloid formation; brain tissue; combat; disease phenotype; disorder control; fly; knock-down; neuroinflammation; neuron loss; novel; overexpression; peroxiredoxin; survivorship; transgene expression

A major pathological feature of Alzheimer's Disease (AD) is neuroinflammation, which has been characterized as both a cause and a consequence of chronic oxidative stress. Oxidative stress and inflammatory reactions are combatted by different antioxidant and redox-regulating factors. One such factor is the thiol-dependent peroxidase, Peroxiredoxin 6 (Prx6), which is known to possess antioxidant function through its peroxidase activity (PRX) and to regulate inflammation through its phospholipase activity (PLA). It is expressed at high levels in Alzheimer's patients and, when overexpressed in a mouse AD model, actually exacerbates the AD phenotype. We propose to use the Drosophila model to test the hypothesis that it is the phospholipase activity in the Prx6 gene that elicits a chronic state of inflammation and contributes to the Alzheimer's phenotype. In Drosophila, there exist two Prx6 variants, one of which (dPrx2540) is equivalent to the bifunctional mammalian form while the other (dPrx6005) does not possess PLA activity. The objectives of this proposal are two-fold. In Aim 1 both the bifunctional variant dPrx2540 as well as the variant possessing only peroxidase activity (dPrx6005) will be overexpressed in brain tissue to determine their relative impact in AD and control backgrounds, using a battery of tests, including survivorship, neuronal pathology and physical activity. In Aim 2, dPrx6 isoform transgenes will be engineered in which either the peroxidase activity or the phospholipase activity or both are ablated and these will be used to generate transgenic lines. We will then be in a position to determine the differential roles of PLA and PRX activities of the bifunctional dPrx2540 on AD progression. This will be achieved by transgene expression targeted specifically to neuronal tissue in both AD and normal backgrounds. A positive outcome in this endeavor would point to a series of potential targets for translational research, ranging from phospholipase activity to arachidonic acid and other downstream effectors of inflammation.

阿尔茨海默病（AD）的主要病理特征是神经炎症， 已经被表征为慢性氧化应激的原因和结果。 氧化应激和炎症反应是由不同的抗氧化剂和 氧化还原调节因子一个这样的因子是硫醇依赖性过氧化物酶， 过氧化物氧还蛋白6（Prx6），已知其通过其抗氧化活性而具有抗氧化功能。 过氧化物酶活性（PRX）并通过其磷脂酶活性调节炎症 （PLA）。它在阿尔茨海默氏症患者中高水平表达，当在阿尔茨海默氏症患者中过度表达时， 小鼠AD模型，实际上加剧了AD表型。我们建议使用 果蝇模型来检验这一假设，即它是磷脂酶活性的Prx6 一种引发慢性炎症并导致阿尔茨海默氏症的基因 表型在果蝇中，存在两种Prx6变体，其中一种（dPrx2540）是 相当于双功能哺乳动物形式，而另一种（dPrx6005）不 有PLA活动。这项建议有两个目的。在目标1中， 双功能变体dPrx 2540以及仅具有过氧化物酶活性的变体 （dPrx6005）将在脑组织中过表达，以确定它们在AD中的相对影响 和对照背景，使用一系列测试，包括生存率，神经元 病理学和身体活动。在目标2中，将工程化dPrx6同种型转基因 其中过氧化物酶活性或磷脂酶活性或两者都被消除 并且这些将用于产生转基因品系。然后我们将能够 确定双功能dPrx 2540的PLA和PRX活性对 AD进展。这将通过转基因表达来实现，所述转基因表达特异性靶向于 在AD和正常背景两者中的神经元组织中。这方面的积极成果 奋进将指出一系列潜在的目标，转化研究， 从磷脂酶活性到花生四烯酸和其他下游效应物， 炎症