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(负荷)的危险因素是年龄。载脂蛋白E的载脂蛋白4等位基因的遗传是载脂蛋白E负荷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，发生负荷的潜在数量变异可能受多个基因控制。环境因素在AD发病风险和发病机制中的作用日益受到重视。在这方面，关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中，某些染色质标记诱导的变化可以影响痴呆的发展和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(As)暴露在AD病因和进展中所起作用的理解。我们充分利用在我们持续不断的NIEHS R21：1支持下取得的结果：1)成年小鼠如果暴露于与人类相关的砷暴露，可能会进一步恶化它们的认知能力，增加淀粉样斑块和海马区反应性星形细胞增多；3)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，参与记忆形成和认知行为的早期生长反应因子Egr1(早期生长反应1)的表达水平和活性依赖程度较低。3)出生前暴露于AS和高脂饮食(HFD)会导致组蛋白3(H3K9)赖氨酸9的整体低乙酰化和基因乙酰化模式的改变，这些基因的乙酰化模式是多梳抑制复合体PRC1和PRC2的组成部分，通过改变组蛋白修饰来调节全基因组的基因表达。我们假设，产前、围产期和出生后的砷暴露会损害认知储备，并抑制成年生物体对环境侮辱(如HFD)的适应能力。结果是易患AD或加重现有的AD表型，APOE的遗传背景对病理有显著影响。我们提出，组蛋白修饰，包括由PRC2催化的组蛋白修饰和必要转录程序(如LXR和Egr1)的丢失是AS效应的分子机制。为了验证这一假说，我们将实现两个特定的目标：目的1.阐明砷暴露对AD模型小鼠AD样表型发育的影响。目的2：探讨砷暴露后认知功能和AD表型改变的表观遗传学分子机制。

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.