Chronic hypoxia facilitates Alzheimer's disease through demethylation of γ-secretase by downregulating DNA methyltransferase 3b
Chronic hypoxia facilitates Alzheimer's disease through demethylation of γ-secretase by downregulating DNA methyltransferase 3b
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DOI：
10.1016/j.jalz.2015.05.019
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发表时间：
2016-02-01
影响因子：
14
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Liu, Hui;Qiu, Hongyan;Le, Weidong
前言：环境因素和表观遗传机制被认为是导致阿尔茨海默病（AD）的原因。我们以前的研究表明，产前缺氧会加重后代小鼠的认知障碍和神经病理学。方法：将3月龄APP（swe）/PS1（dE 9）小鼠暴露于低氧环境中，每天6 h，连续30 d，分别于4、6、9月龄进行学习记忆、生化和神经病理学检查。慢性缺氧可诱导小鼠基因组DNA去甲基化，降低DNA甲基转移酶3b（DNMT 3b）的表达。我们进一步发现，DNMTs抑制升高淀粉样前体蛋白，β-和γ-分泌酶的蛋白质水平，而DNMT 3b的过度表达抑制了它们的水平在vitro.Discussion：我们的研究表明，慢性缺氧可以通过DNMT 3b的下调，通过编码γ-分泌酶组分的基因的去甲基化来加重AD的进展。(C)2016年阿尔茨海默氏症协会。爱思唯尔公司出版All rights reserved.
Introduction: Environmental factors and epigenetic mechanisms are believed to contribute to Alzheimer's disease (AD). We previously documented that prenatal hypoxia aggravated the cognitive impairment and neuropathology in offspring mice. Here, we investigate the chronic hypoxiainduced epigenetic modifications in AD.Methods: The 3-month-old APP(swe)/PS1(dE9) mice were exposed to hypoxic environment 6 hour/day for 30 days, followed by learning and memory tests and biochemical and neuropathology measurement at the age of 4, 6, and 9 months.Results: We found hypoxia exaggerated the neuropathology and cognitive impairment in AD mice. Chronic hypoxia induced demethylation on genomic DNA and decreased the expression of DNA methyltransferase 3b (DNMT3b) in vivo. We further found that DNMTs inhibition elevated the protein levels of amyloid precursor protein, beta- and gamma-secretases, whereas overexpression of DNMT3b suppressed the levels of them in vitro.Discussion: Our study suggests chronic hypoxia can aggravate AD progression through demethylation of genes encoding gamma-secretase components by downregulation of DNMT3b. (C) 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.