Epigenomic impact of diet and toxicant exposure in Alzheimers disease etiology

描述(由申请人提供)：阿尔茨海默病(AD)易感性的潜在数量变化由多个基因、环境因素和代谢信号控制。重要的是，一些代谢刺激，如高胆固醇血症、肥胖、高胰岛素血症和胰岛素抵抗，遵循一定的饮食模式和生活方式，并与老年痴呆症和AD风险增加有关。最近，高脂饮食(HFD)对认知功能的不利影响以及脑淀粉样变性和淀粉样血管病的恶化在AD的动物模型中得到了证实。同样重要的是，暴露于一些有毒的环境因素，如饮用水砷(As)，可引起与AD的病理和临床特征无法区分或一致的变化，包括：诱导tau蛋白过度磷酸化，淀粉样前体蛋白(APP)上调；心血管疾病增加；脑炎症反应增强，小鼠高胰岛素血症，以及认知和记忆障碍。然而，目前还完全不清楚HFD和环境暴露是否会增加AD风险和疾病进展。饮食因素或AS暴露引起的表观遗传重编程的新研究和新发现有力地表明，组蛋白标记的诱导变化在一生中保留并积累，以促进AD的发病。因此，年龄相关的基因-环境相互作用对迟发性AD(LOAD)的发生和发展至关重要。因此，假设HFD和AS对表观遗传染色质修饰的联合影响会导致致病组织和器官选择性转录活动，从而增加发展、加速或加重AD表型的风险。拟议研究的目的是：1)在一个成熟的AD动物模型中，揭示在HFD和AS暴露的共同作用下，大脑和肝脏染色质修饰的器官特异性变化，从而产生全基因组致病转录活性；2)揭示由已发现的组蛋白修饰变化引起的联合暴露引起的AD表型特有的变化(认知表现、脑实质中淀粉样蛋白沉积、代谢异常和血管壁重塑)。这一目标将通过实现以下具体目标来实现：目标1：揭示集体暴露于HFD和AS对AD表型和脂肪和葡萄糖代谢的影响；以及目标2：评估HFD和AS诱导的AD小鼠脑和肝脏染色质修饰的变化，并将表观基因组的特异性变化与行为缺陷和脑淀粉样变性联系起来。 公共卫生相关性：这项研究将解决对与人类健康高度相关的领域--阿尔茨海默病--的持续研究至关重要的问题，特别是在砷暴露后，营养和环境信号引起的染色质修饰的变化，以及它们在这种疾病的发展和进展中的作用。这项研究的结果将有助于我们理解参与脑内胆固醇运输的重要基因和蛋白质之间的相互作用，以及关于这些蛋白质功能紊乱的知识如何有助于开发新的治疗策略来减缓AD的进展。

DESCRIPTION (provided by applicant): The underlying quantitative variation in susceptibility to develop Alzheimer's disease (AD) is controlled by multiple genes, environmental factors, and metabolic signals. Importantly, some metabolic stimuli, like hypercholesterolemia, obesity, hyperinsulinemia and insulin resistance, follow certain dietary patterns and lifestyle, and are associated with increased risk of dementia and AD at advanced age. The detrimental effects of high fat diet (HFD) on cognitive performance and exacerbation of cerebral amyloidosis and amyloid angiopathy has been recently demonstrated in an animal model of AD. Equally important, exposure to some toxic environmental factors, such as drinking water arsenic (As), induces changes that are indistinguishable from, or coincide with pathological and clinical features of AD including: induced tau hyperphosphorylation, upregulation of amyloid precursor protein (APP); increased cardiovascular disease; enhanced brain inflammatory reactions, hyperinsulinemia in mice, and cognitive and memory deficits. It is completely unknown, however, whether HFD and environmental exposures combine to increase AD risk and disease progression. Emerging research and novel findings of epigenetic reprogramming inflicted by dietary agents or As exposure strongly suggest that induced changes in histone marks are retained throughout the life and accumulate to promote AD pathogenesis. Thus age dependent gene-environment interactions are critical for the development and progression of late onset AD (LOAD). It is therefore hypothesized that the combined impact of HFD and As on epigenetic chromatin modifications results in pathogenic tissue and organ-selective transcriptional activity that translates into increased risk of developing, accelerating or aggravating AD phenotypes. The objectives of the proposed research are: 1) In a well-established animal model for AD, to reveal organ specific changes in chromatin modifications in brain and liver, instigated by the collective effect of HFD and As exposure that produce genome wide pathogenic transcriptional activity, and 2) To reveal changes specific for AD phenotype (cognitive performance, amyloid deposition in brain parenchyma, metabolic abnormality and blood vessel wall remodeling) caused by combined exposures that result from identified changes in histone modifications. This goal will be achieved by accomplishing the following Specific Aims: Aim 1: To reveal the consequences of collective exposure to HFD and As on AD phenotype and lipid and glucose metabolism; and Aim 2: To assess changes in chromatin modifications in brain and liver induced by HFD and As in AD mice and to correlate specific changes in the epigenome to behavioral deficits and brain amyloidosis. PUBLIC HEALTH RELEVANCE: This study will address questions that are important for continuing research in a field highly relevant to human health - Alzheimer's disease and changes in chromatin modifications induced by nutritional and environmental signals specifically after arsenic exposure, and their role in the development and progression of this disease. The result from this study will help us to understand the interplay between important genes and proteins involved in cholesterol transport in brain, and how the knowledge about disturbed function of those proteins can help in developing new therapeutic strategies for slowing AD progression.