Epigenetic and phenotypic effects of arsenic: impacts on cognition and AD

描述（由申请人提供）：到目前为止，唯一确定的散发性晚发型AD （LOAD）的风险因素是年龄。载脂蛋白E的APOE¿4等位基因的遗传是LOAD的主要遗传危险因素，但这种易感性的分子机制尚不清楚。可能与其他多因素（全身性）疾病类似，LOAD易感性的潜在数量变化可能由多个基因控制。环境因素在阿尔茨海默病发病机制中的作用越来越受到重视。在这方面，对暴露于环境因素造成的表观遗传重编程的研究强烈表明，在发育和出生后生活中某些染色质标记的变化可以影响痴呆症的发展和AD的进展。我们建议在动物模型中进行研究，以促进对环境砷暴露在AD病因和进展中的作用的理解。我们利用正在进行的NIEHS R21支持下产生的结果：1)将已经发展为AD表型的成年小鼠暴露于与人类相关的饮用水中As浓度（100¿g/ml）会进一步恶化其认知能力，增加淀粉样斑块和海马体中的反应性星形细胞增多；核肝X受体（LXR）和重要靶基因的表达降低。2)暴露于as的幼鼠认知功能受损，与记忆形成和认知表现有关的转录因子EGR1（早期生长反应1）的表达水平和活性依赖性较低。3)产前暴露于砷和高脂肪饮食（HFD）会导致组蛋白3 （H3K9）赖氨酸9的整体低乙酰化，以及通过组蛋白修饰改变调节基因全基因组表达的多梳抑制复合物PRC1和PRC2组分基因乙酰化模式的改变。我们假设产前、围产期和产后暴露会损害认知储备，抑制成年机体对环境损伤（如HFD）的适应能力。结果是阿尔茨海默病的易感性或加重现有的阿尔茨海默病表型，APOE遗传背景显著影响病理。我们提出，组蛋白修饰，包括PRC2催化的修饰和基本转录程序（如LXR和EGR1）的缺失是这些作用的分子机制。为了验证这一假设，我们将实现两个具体目标：目标1。目的：探讨砷暴露对AD模型小鼠AD样表型发育的影响。目的2：确定暴露后认知表现和AD表型变化的表观遗传分子机制。

DESCRIPTION (provided by applicant): The only risk factor identified so far for sporadic late onset AD (LOAD) is aging. The inheritance of APOE¿4 allele of apolipoprotein E is the major genetic risk factor for LOAD but molecular mechanisms underlying this susceptibility are unknown. It is possible that similar to other multifactorial (systemic) diseases, the underlying quantitative variation in susceptibility to develop LOAD is probably controlled by multiple genes. The role of environmental factors in the risk and pathogenesis of AD has been increasingly appreciated. In this regard, the research on epigenetic reprogramming inflicted by exposure to environmental factors, strongly suggests that changes induced at certain chromatin marks during the development and postnatal life can influence development of dementia and AD progression. We are proposing investigation in animal models to advance the understanding of the role of environmental arsenic (As) exposure in the etiology and progression of AD. We capitalize on the results generated with the support of our ongoing NIEHS R21: 1) exposure of adult mice, with already developed AD phenotype, to human relevant As concentrations (100 ¿g/ml) in drinking water further deteriorates their cognitive performance, increases amyloid plaques and reactive astrocytosis in hippocampus; the expression of nuclear liver X receptors (LXR) and important target genes, is decreased. 2) Young mice exposed to as are cognitively impaired and the expression level of and activity dependent transcription factor EGR1 (Early growth response 1), implicated in memory formation and cognitive performance is lower. 3) prenatal exposure to As and high fat diet (HFD) causes global hypoacetylation at Lysine 9 of histone 3 (H3K9) and alterations in acetylation pattern of genes, components of Polycomb Repressive Complexes PRC1 and PRC2, that modulate gene expression genome-wide through changes in histone modifications. We hypothesize that prenatal, perinatal and postnatal as exposure impairs cognitive reserve and inhibits adaptive capacity of the adult organism to environmental insults (e.g. HFD). The outcome is a predisposition to AD or aggravated existing AD phenotype, with the APOE genetic background significantly impacting the pathology. We are proposing that histone modifications, including those catalyzed by PRC2 and loss of essential transcriptional programs (e.g. LXR and EGR1) are molecular mechanisms underlying as effects. To test the hypothesis we will accomplish two Specific Aims: Aim 1. To elucidate the effects of as exposure on the development of AD-like phenotype in AD model mice. Aim 2: To identify epigenetic molecular mechanisms underlying changes in cognitive performance and AD phenotype in response to as exposure.