Pesticides, Paraoxonase and Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）最常与脑中淀粉样蛋白-β（Abeta）肽的沉积相关。脑中Abeta肽的存在在聚集体的形成中起重要作用，所述聚集体可导致神经元损伤、功能障碍、小胶质细胞活化和AD的神经病理学特征。Abeta [有或没有tau/神经元缠结（NFT）]主要通过氧化应激干扰细胞特性，这破坏了细胞的抗氧化防御机制。最近的研究表明，环境毒素（environmental toxins，ESTs）可能参与AD和神经退行性疾病的致病过程，破坏神经元功能，导致氧化应激（oxidative stress，OS）、炎症和细胞死亡。我们和其他人已经表明，对氧磷酶-1（PON-1）的活性在AD患者的血浆中降低，并且在APP转基因小鼠中，ADP（有机磷酸盐）会加剧AD的发病机制。我们假设AD部分是由于早期（胚胎/新生儿）或慢性低水平暴露于β-羟考酮或对氧磷酶活性缺陷引起血浆和脑中ET水平升高，引发氧化应激、炎症和Abeta产生。这种模式促进Abeta聚集并加剧细胞扰动和AD发病机制。本提案的重点是了解有机磷（OPs作为象征性的磷）的功能和磷和对氧磷酶（PON-1）之间的相互关系，在氧化应激和炎症与AD。该提案的长期目标是了解P2P和PON-1在氧化应激中的作用，以确定毒素水平的改变是否是AD患者的潜在治疗策略。为此，将测试以下具体目标：具体目标1：确定有机磷酸酯（OP）对APP转基因小鼠中AD发病机制的影响。目的二：研究对氧磷酶1缺乏对APP转基因小鼠AD发病机制的影响。具体目的3：研究加兰他敏和腺病毒介导的PON 1对有机磷诱发的AD的治疗作用。具体目标4：确定PON 1同种异型或PON 1活性的功能缺陷是否可预测环境毒素刺激的AD的发生和进展。这些研究将有助于明确环境因素在AD发病机制中的作用。公共卫生相关性：该项目的总体目标是确定环境毒素（ESTs）在AD和神经退行性疾病的致病过程中的作用。我们假设AD部分是由于早期（胚胎/新生儿）或慢性低水平暴露于β-羟考酮或对氧磷酶活性缺陷引起血浆和脑中ET水平升高，引发氧化应激、炎症和Abeta产生。本提案的重点是了解有机磷（OPs作为象征性的磷）的功能和磷和对氧磷酶（PON- 1）之间的相互关系，在氧化应激和炎症与AD。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is most commonly associated with deposition of amyloid-beta (Abeta) peptide in the brain. The presence of Abeta peptide in the brain plays an important role in the development of aggregates that may result in neuronal damage, dysfunction, microglial activation and neuropathological features of AD. Abeta [with or without tau/neurofibrillary tangles (NFTs)] perturbs cellular properties mainly by oxidant stress, which overwhelms the cellular antioxidant defense mechanisms. Recent studies suggest that environmental toxins (ETs) may contribute to the pathogenic process of AD and neurodegenerative diseases, disrupting neuronal function resulting in oxidative stress (OS), inflammation and cell death. We and others have shown that paraoxonase-1 (PON-1) activity is reduced in the plasma of individuals with AD, and that ETs (organophosphates) exacerbate AD pathogenesis in APP transgenic mice. We hypothesize that AD partially results from early (embryonic/neonatal) or chronic low level exposure to ETs or a defect in paraoxonase activity that gives rise to increased ET levels in plasma and brain triggering oxidative stress, inflammation and Abeta production. This paradigm facilitates Abeta aggregation and exacerbates cellular perturbation and AD pathogenesis. The focus of this proposal is to understand the function of organophosphates (OPs as symbolic ETs) and interrelationship between ETs and paraoxonase (PON-1) in oxidative stress and inflammation associated with AD. The long-term goal of this proposal is to understand the role of ETs and PON-1 in oxidative stress in order to determine if alteration in the level of toxins is a potential therapeutic strategy for individuals with AD. To this end, the following specific aims will be tested: Specific Aim 1: To determine the effect of organophosphates (OPs) on AD pathogenesis in APP transgenic mice. Specific Aim 2: To determine the effect of paraoxonase 1 deficiency on organophosphate induced AD pathogenesis in APP transgenic mice. Specific Aim 3: To study the therapeutic effects of galantamine and adenoviral delivered PON1 on organophosphate provoked AD. Specific Aim 4: To determine if PON1 allotype or functional deficits in PON1 activity predict the development and progression of AD that may be stimulated by environmental toxins. These studies will help to define the role of environmental factors in the pathogenesis of AD. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to determine the role of environmental toxins (ETs) in their contribution to the pathogenic process of AD and neurodegenerative diseases. We hypothesize that AD partially results from early (embryonic/neonatal) or chronic low level exposure to ETs or a defect in paraoxonase activity that gives rise to increased ET levels in plasma and brain triggering oxidative stress, inflammation and Abeta production. The focus of this proposal is to understand the function of organophosphates (OPs as symbolic ETs) and interrelationship between ETs and paraoxonase (PON- 1) in oxidative stress and inflammation associated with AD.