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.

阿尔茨海默氏病（AD）的主要病理特征是神经炎症，它 已被描述为慢性氧化应激的原因和结果。 氧化应激和炎症反应被不同的抗氧化剂和 氧化还原调节因素。这样一个因素是硫醇依赖性过氧化物酶， 过氧蛋白6（PRX6），已知通过其具有抗氧化功能 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以高水平表达 鼠标广告模型，实际上加剧了AD表型。我们建议使用 果蝇模型测试了它是PRX6中的磷脂酶活性的假设 引起慢性炎症状态并导致阿尔茨海默氏症的基因 表型。在果蝇中，存在两个PRX6变体，其中之一（dprx2540）是 相当于双功能的哺乳动物形式，而另一种（dprx6005）则不 具有PLA活性。该提议的目标是两个方面。在AIM 1中 双功能变体DPRX2540以及仅具有过氧化物酶活性的变体 （DPRX6005）将在脑组织中过度表达，以确定其在AD中的相对影响 和控制背景，使用一系列测试，包括生存，神经元 病理和体育锻炼。在AIM 2中，DPRX6同工型转基因将设计 其中的过氧化物酶活性或磷脂酶活性或两者都是消融 这些将用于生成转基因线。然后，我们将处于 确定双功能DPRX2540在PLA和PRX活动上的差异作用 广告进展。这将通过针对针对的转基因表达来实现 AD和正常背景的神经元组织。这是积极的结果 努力将指出转化研究的一系列潜在目标， 从磷脂酶活性到花生四烯酸和其他下游效应子 炎。