Epigenetics, oxidative stress, and Alzheimer disease.
Epigenetics, oxidative stress, and Alzheimer disease.
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DOI：
10.1016/j.freeradbiomed.2009.02.006
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发表时间：
2009-05-01
影响因子：
7.4
通讯作者：
Cardozo-Pelaez, Fernando
中科院分区：
文献类型：
--
作者：
Zawia, Nasser H.;Lahiri, Debomoy K.;Cardozo-Pelaez, Fernando
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其临床表现出现在老年。90%的AD病例的散发性质、不同的易感性和病程以及该疾病的晚期发病表明表观遗传和环境因素在迟发性AD（LOAD）的病因中发挥着作用。动物暴露研究表明，AD可能在生命早期开始，并可能涉及环境，表观遗传学和氧化应激之间的相互作用。啮齿动物和灵长类动物的早期生活暴露于异生金属铅（Pb）增强了与AD相关的基因的表达，抑制了其他基因的表达，并增加了老年大脑中氧化DNA损伤的负担。控制基因表达和促进氧化DNA损伤积累的表观遗传机制是通过CpG二核苷酸甲基化或氧化的改变介导的。我们发现，在大脑发育过程中发生的环境影响抑制DNA甲基转移酶，从而使与AD相关的基因（如β-淀粉样前体蛋白（APP））的启动子低甲基化。这种早期生命印记在生命后期持续并触发，以增加APP和淀粉样蛋白β（Aβ）的水平。Aβ水平升高促进了活性氧（ROS）的产生，从而损伤DNA并加速神经退行性事件。虽然AD相关基因在生命后期过度表达，但其他基因受到抑制，这表明这些早期生命扰动导致基因的低甲基化和高甲基化。高甲基化基因对Aβ增强的氧化性DNA损伤敏感，因为甲基胞嘧啶限制了相邻羟基鸟苷的修复。虽然导致特定基因的早期低甲基化或高甲基化的条件尚不清楚，但这些变化可能会影响基因表达，并影响老年大脑对氧化DNA损伤的易感性。
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The sporadic nature of 90% of AD cases, the differential susceptibility and course of illness, as well as the late age onset of the disease suggest that epigenetic and environmental components play a role in the etiology of late onset AD (LOAD). Animal exposure studies demonstrated that AD may begin early in life and may involve the interplay between the environment, epigenetics and oxidative stress. Early life exposure of rodents and primates to the xenobiotic metal lead (Pb) enhanced the expression of genes associated with AD, repressed the expression of others, and increased the burden of oxidative DNA damage in the aged brain. Epigenetic mechanisms that control gene expression and promote the accumulation of oxidative DNA damage are mediated through alterations in the methylation or oxidation of CpG dinucleotides. We found that environmental influences occurring during brain development inhibit DNA methyltransferases, thus hypomethylating promoters of genes associated with AD such as the beta- amyloid precursor protein (APP). This early life imprint was sustained and triggered later in life to increase the levels of APP and amyloid-beta (Aβ). Increased Aβ levels promoted the production of reactive oxygen species (ROS) which damage DNA and accelerate neurodegenerative events. While AD-associated genes were over-expressed late in life, others were repressed, suggesting that these early life perturbations result in hypomethylation as well as hypermethylation of genes. The hypermethylated genes are rendered susceptible to Aβ-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. While the conditions leading to early life hypo or hyper methylation of specific genes are not known, these changes can impact gene expression and imprint susceptibility to oxidative DNA damage in the aged brain.
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DOI：
10.1080/07315724.2004.10719428
发表时间：
2004-12-01
影响因子：
3.5
作者：
Barker, DJP
通讯作者：
Barker, DJP
影响因子：
7.7
作者：
Barker, DJP;Eriksson, JG;Osmond, C
通讯作者：
Osmond, C
影响因子：
7.4
作者：
Cecchi, Cristina;Fiorillo, Claudia;Liguri, Gianfranco
通讯作者：
Liguri, Gianfranco
影响因子：
4.1
作者：
Cao, YX;Jean, JC;Williams, MC
通讯作者：
Williams, MC
影响因子：
64.8
作者：
Bhattacharya, SK;Ramchandani, S;Szyf, M
通讯作者：
Szyf, M