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）易感性的潜在定量变化受多个基因、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，遵循某些饮食模式和生活方式，并与老年痴呆症和AD的风险增加有关。高脂饮食（HFD）对认知能力和脑淀粉样变性和淀粉样血管病恶化的有害影响最近已在AD动物模型中得到证实。同样重要的是，暴露于一些有毒环境因素，如饮用水砷（As），诱导的变化与AD的病理和临床特征难以区分或一致，包括：诱导的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;增强的脑炎症反应，小鼠高胰岛素血症，以及认知和记忆缺陷。然而，HFD和环境暴露联合收割机是否会增加AD风险和疾病进展还完全未知。新兴的研究和新发现的表观遗传重编程所造成的饮食剂或作为曝光强烈表明，诱导的组蛋白标记的变化保留在整个生命和积累，以促进AD的发病机制。因此，年龄依赖性基因-环境相互作用对晚发性AD（LOAD）的发生和进展至关重要。因此，假设HFD和As对表观遗传染色质修饰的组合影响导致致病组织和器官选择性转录活性，其转化为发展、加速或加重AD表型的风险增加。拟议研究的目标是：1）在AD的良好建立的动物模型中，揭示脑和肝中染色质修饰的器官特异性变化，这是由产生全基因组致病性转录活性的HFD和As暴露的集体效应引起的，以及2）揭示AD表型特异性的变化在某些实施方案中，所述组合暴露可导致由组蛋白修饰的确定的变化引起的组合暴露（认知表现、脑实质中的淀粉样蛋白沉积、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表型以及脂质和葡萄糖代谢的后果;目标2：评估AD小鼠中由HFD和As诱导的脑和肝脏中染色质修饰的变化，并将表观基因组中的特定变化与行为缺陷和脑淀粉样变性相关联。

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.