Peroxiredoxin 6 and Alzheimer's

阿尔茨海默病(AD)的一个主要病理特征是神经炎症，它 已经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由不同的抗氧化剂和 氧化还原调节因子。其中一个因素是依赖于硫醇的过氧化物酶， 过氧化还蛋白6(Prx6)，已知具有抗氧化功能，通过其 过氧化物酶活性(PRX)，并通过其磷脂酶活性调节炎症 (解放军)。它在阿尔茨海默病患者中高水平表达，当在 一种小鼠AD模型，实际上加剧了AD的表型。我们建议使用 果蝇模型检验假设是Prx6中的磷脂酶活性 导致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，存在两种Prx6变体，其中之一(DPrx2540)是 相当于双功能哺乳动物的形式，而另一个(DPrx6005)不是 具有解放军活性。这项提案的目标有两个。在目标1中， 双功能变异体dPrx2540以及仅具有过氧化物酶活性的变异体 (DPrx6005)将在脑组织中过表达，以确定它们在AD中的相对影响 以及控制背景，使用一系列测试，包括存活率、神经元 病理学和体力活动。在目标2中，将对dPrx6亚型转基因进行工程 其中过氧化物酶活性或磷脂酶活性或两者都被消融 这些将被用来产生转基因品系。届时我们将能够 确定双功能dPrx2540的pla和prx活性的不同作用 广告进展。这将通过专门针对以下目标的转基因表达来实现 阿尔茨海默病和正常背景的神经元组织。这是一个积极的结果 Endavor将指出一系列潜在的翻译研究目标，范围包括 从磷脂酶活性到花生四烯酸和其他下游效应因子 发炎。

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.