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

描述（由申请人提供）：到目前为止，唯一确定的散发性迟发性AD（LOAD）的风险因素是衰老。APOE的遗传载脂蛋白E的4等位基因是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。这是可能的，类似于其他多因素（系统性）疾病，潜在的定量变化的易感性发展负载可能是由多个基因控制。环境因素在AD发病中的作用越来越受到重视。在这方面，对暴露于环境因素引起的表观遗传重编程的研究强烈表明，在发育和出生后生活期间在某些染色质标记处诱导的变化可以影响痴呆和AD进展的发展。我们建议在动物模型中进行调查，以促进对环境砷（As）暴露在AD病因学和进展中的作用的理解。我们利用在我们正在进行的NIEHS R21的支持下产生的结果：1）将已发展为AD表型的成年小鼠暴露于饮用水中的人类相关As浓度（100 μ g/ml），进一步恶化其认知能力，增加海马中的淀粉样蛋白斑块和反应性星形胶质细胞增生;核肝X受体（LXR）和重要靶基因的表达降低。2)暴露于砷的年轻小鼠认知受损，并且与记忆形成和认知表现有关的活性依赖性转录因子EGR1（早期生长反应1）的表达水平较低。3)产前暴露于As和高脂饮食（HFD）导致组蛋白3（H3K9）的赖氨酸9处的整体低乙酰化和基因（多梳抑制复合物PRC 1和PRC 2的组分）的乙酰化模式的改变，所述多梳抑制复合物PRC 1和PRC 2通过组蛋白修饰的变化来调节基因表达。我们假设，产前，围产期和产后的作为暴露损害认知储备，抑制适应能力的成年有机体环境的侮辱（如HFD）。其结果是易患AD或加重现有AD表型，APOE遗传背景显著影响病理学。我们认为，组蛋白修饰，包括PRC2催化的组蛋白修饰和基本转录程序（如LXR和EGR1）的丢失是作为效应的分子机制。为了验证这个假设，我们将实现两个具体目标：目标1。探讨砷暴露对AD模型小鼠AD样表型形成的影响。目的2：研究砷暴露后认知功能和AD表型改变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.