Oxidative stress, Homocysteine and Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是最常见的痴呆症形式，目前还没有有效的治疗方法。虽然导致该病的致病因素(S)尚不清楚，但很明显，一些环境因素与内源性因素相互作用，可能在其发病机制中发挥作用。流行病学研究表明，血液中高水平的同型半胱氨酸(Hcy)，一种被称为高同型半胱氨酸血症(HHcy)的情况，是发展为AD的危险因素。同型半胱氨酸来源于蛋氨酸的转化，这种转化依赖于必需的维生素(即B6、B12和叶酸)的存在。由于体外细胞暴露于同型半胱氨酸可诱导氧化应激和炎症反应，我们想要验证这样一种假设，即这些机制在体内调节AD和HHcy之间的联系。此前，我们已经证明，在AD大脑的选择性区域以及与疾病严重程度相关的AD患者中，脂质过氧化反应增加。炎症也会发生在AD中，它确实与局部和外周炎症反应的全部复杂性有关。过度表达瑞典突变的淀粉样前体蛋白(Tg2576)的转基因小鼠显示出大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对两种不同的AD样淀粉样变性模型(Tg2576和APP/YAC TG小鼠)的影响。首先，我们将验证饮食诱导的HHcy会加剧这些小鼠的大脑氧化应激和炎症，加速行为损伤和脑淀粉样蛋白/3肽沉积的假设。其次，通过将AD TG小鼠与缺乏Hcy代谢关键酶的TG小鼠杂交，我们将调查遗传诱导的HHcy是否会加剧大脑氧化应激、炎症反应、行为障碍以及淀粉样β蛋白的水平和沉积。 综上所述，这项建议验证了长期暴露于高Hcy水平会加剧两种不同的AD样淀粉样变性小鼠模型中AD样表型的假设，并研究了可能解释这种影响的一些分子和细胞机制。在旨在降低AD风险患者Hcy水平的预防研究开始之前，这些研究将是必要的基础。

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.