Oxidative stress, Homocysteine and Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆症形式，目前尚无有效的治疗方法。虽然导致该病的致病事件尚不清楚，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起作用。流行病学研究表明，血液中高水平的同型半胱氨酸（Hcy），即高同型半胱氨酸血症（HHcy）是患AD的一个危险因素。Hcy来源于蛋氨酸的转化，这种转化依赖于必需维生素（即B6、B12和叶酸）的存在。由于细胞暴露于体外Hcy诱导氧化应激和炎症反应，我们想验证这些机制在体内介导AD和HHcy之间联系的假设。之前，我们已经证明脂质过氧化在AD大脑的选择性区域增加，并且在AD患者中与疾病严重程度相关。炎症也发生在AD中，它确实与局部和外周炎症反应的复杂性有关。过度表达淀粉样蛋白前体蛋白瑞典突变（Tg2576）的转基因小鼠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对两种不同ad样淀粉样变性模型（Tg2576和APP/YAC Tg小鼠）的影响。首先，我们将在这些小鼠中验证饮食诱导的HHcy加剧大脑氧化应激和炎症，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，我们将研究遗传诱导的HHcy是否会加剧脑氧化应激、炎症反应、行为障碍和淀粉样蛋白肽水平和沉积。

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.