Folic acid attenuates the effects of amyloid β oligomers on DNA methylation in neuronal cells
Folic acid attenuates the effects of amyloid β oligomers on DNA methylation in neuronal cells
复制标题
叶酸减弱淀粉样蛋白 β 寡聚体对神经元细胞 DNA 甲基化的影响
DOI：
10.1007/s00394-015-1002-2
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发表时间：
2016-08-01
影响因子：
5
通讯作者：
Huang, Guowei
中科院分区：
文献类型：
--
作者：
Liu, Huan;Li, Wen;Huang, Guowei
阿尔茨海默病(AD)是一种高度流行的痴呆症。基因甲基化的表观遗传机制提供了营养、一碳代谢和疾病进展之间的假定联系，因为叶酸缺乏可能导致AD相关基因启动子区域的低甲基化。在AD模型中，补充叶酸可能通过调节APP和PS1的DNA甲基化来保护神经元细胞免受淀粉样β蛋白(Aβ)寡聚体诱导的毒性。原代培养的海马神经元细胞和海马HT-22细胞分别与叶酸、Aβ寡聚体或赋形剂共同孵育24 h，然后与不同浓度的叶酸孵育72 h。AD转基因小鼠分别饲喂叶酸缺乏饲料和对照饲料，每天灌胃不同剂量的叶酸(0或600µg/kg)。检测DNA甲基转移酶(DNMT)活性、细胞活力、细胞甲基化潜能、APP和PS1的表达以及各自启动子的甲基化。叶酸剂量依赖性地刺激甲基化潜能和DNMT活性，改变PS1和APP启动子的甲基化，降低PS1和APP的表达，并部分维持细胞活力。叶酸增加AD转基因小鼠PS1和APP启动子的甲基化。这些结果提示叶酸可能通过抑制Aβ寡聚体诱导的神经元毒性而起作用。
Alzheimer's disease (AD) is a highly prevalent type of dementia. The epigenetic mechanism of gene methylation provides a putative link between nutrition, one-carbon metabolism, and disease progression because folate deficiency may cause hypomethylation of promoter regions in AD-relevant genes. We hypothesized that folic acid supplementation may protect neuron cells from amyloid beta (A beta) oligomer-induced toxicity by modulating DNA methylation of APP and PS1 in AD models.Primary hippocampal neuronal cells and hippocampal HT-22 cells were incubated for 24 h with a combination of folic acid and either A beta oligomers or vehicle and were then incubated for 72 h with various concentrations of folic acid. AD transgenic mice were fed either folate-deficient or control diets and gavaged daily with various doses of folic acid (0 or 600 mu g/kg). DNA methyltransferase (DNMT) activity, cell viability, methylation potential of cells, APP and PS1 expression, and the methylation of the respective promoters were determined.A beta oligomers lowered DNMT activity, increased PS1 and APP expression, and decreased cell viability. Folic acid dose-dependently stimulated methylation potential and DNMT activity, altered PS1 and APP promoter methylation, decreased PS1 and APP expression, and partially preserved cell viability. Folic acid increased PS1 and APP promoter methylation in AD transgenic mice.These results suggest a mechanism by which folic acid may prevent A beta oligomer-induced neuronal toxicity.