Oxidative stress, Homocysteine and Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆症，目前尚无有效的治疗方法。虽然致病事件（S）负责的疾病是未知的，很明显，一些环境因素通过与内源性因素相互作用，可以在其发病机制中发挥作用。流行病学研究表明，高同型半胱氨酸（Hcy）的血液水平，称为高同型半胱氨酸血症（HHcy）的条件是发展AD的危险因素。Hcy来源于甲硫氨酸通过依赖于必需维生素存在的反应的转化（即，B6、B12和叶酸）。由于细胞在体外暴露于同型半胱氨酸诱导氧化应激和炎症反应，我们想测试的假设，这些机制介导在体内AD和HHcy之间的联系。以前，我们已经表明，脂质过氧化增加，在AD大脑的选择性领域，并在AD患者，它与疾病的严重程度。炎症也发生在AD中，并且它确实与局部和外周炎症反应的全部复杂性有关。转基因小鼠过度表达淀粉样前体蛋白（Tg 2576）的瑞典突变表现出脑脂质过氧化和炎症的迹象。我们的长期目标是确定长期暴露于HHcy在两种不同的AD样淀粉样变性模型（Tg 2576和APP/YAC Tg小鼠）中的作用。首先，我们将测试饮食诱导的HHcy加剧脑氧化应激和炎症，加速行为障碍和脑淀粉样蛋白/3肽沉积在这些小鼠中的假设。第二，通过杂交繁殖AD Tg小鼠与Tg小鼠，缺乏同型半胱氨酸代谢的关键酶，我们将调查是否遗传诱导的同型半胱氨酸加剧脑氧化应激，炎症反应，行为障碍，淀粉样β肽水平和沉积。 总之，本研究的目的是在两种不同的AD样淀粉样变性小鼠模型中验证长期暴露于高Hcy水平会加重AD样表型的假设，并研究一些可能导致这种效应的分子和细胞机制。这些研究将是在AD风险患者中开展旨在降低Hcy水平的预防研究之前的必要基础。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia for which there is no effective therapy. Although the causative events(s) responsible for the disease is not known, it is evident that some environmental elements by interacting with endogenous factors could play a role in its pathogenesis. Epidemiological studies have shown that high blood levels of homocysteine (Hcy), a condition known as hyperhomocysteinemia (HHcy) is a risk factor for developing AD. Hcy derives from the conversion of methionine through reactions that are dependent on the presence of necessary vitamins (i.e., B6, B12 and folate). Since cellular exposure in vitro to Hcy induces oxidative stress and inflammatory reactions, we want to test the hypothesis that these mechanisms mediate in vivo the link between AD and HHcy. Previously, we have shown that lipid peroxidation is increased in selective areas of AD brains, and in AD patients where it correlates with disease severity. Inflammation also occurs in AD, and it does do with the full complexity of local and peripheral inflammatory responses. Transgenic mice over-expressing the Swedish mutation of the amyloid precursor protein (Tg2576) manifest signs of brain lipid peroxidation and inflammation. Our longterm goal is to define the effects of long-term exposure to HHcy in two different models of AD-like amyloidosis (Tg2576 and the APP/YAC Tg mice). First, we will test the hypothesis that diet-induced HHcy exacerbates brain oxidative stress and inflammation, accelerates behavioral impairments and brain amyloid/3 peptide deposition in these mice. Second, by cross-breeding AD Tg mice with Tg mice that are deficient for a key enzyme in Hcy metabolism, we will investigate whether genetic-induced HHcy exacerbates brain oxidative stress, inflammatory responses, behavioral impairments, and amyloid beta peptide levels and deposition. In summary, this proposal tests the hypothesis that long-term exposure to high Hcy levels exacerbates ADlike phenotype in two different mouse models of AD-like amyloidosis, and investigates some of the molecular and cellular mechanisms that could account for this effect. These studies will be a necessary basis before prevention studies aimed to reduce Hcy levels are initiated in patients at risk for AD.