中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (7): 1247-1254.doi: 10.4103/1673-5374.251333

• 原著:退行性病与再生 • 上一篇    下一篇

高蛋氨酸和低叶酸与低维生素B6 / B12的饮食与netrin-1表观遗传沉默致记忆丧失相关

  

  • 出版日期:2019-07-15 发布日期:2019-07-15
  • 基金资助:

    NIH基金（HL-107640）

A high methionine, low folate and vitamin B6/B12 containing diet can be associated with memory loss by epigenetic silencing of netrin-1

Anuradha Kalani 1 , Pankaj Chaturvedi 1 , Komal Kalani 2, 3 , Pradip K. Kamat 1 , Poonam Chaturvedi 4 , Neetu Tyagi 1   

  1. 1 Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA
    2 Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
    3 Pharmacology Department and Toxicology, Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA
    4 Department of Neurology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
  • Online:2019-07-15 Published:2019-07-15
  • Contact: Anuradha Kalani, MS, PhD, anukalani@gmail.com; a0kala02@exchange.louisville.edu; Pankaj Chaturvedi, PhD, pcjuly4@gmail.com.
  • Supported by:

    Part of this study was supported by NIH grant HL-107640 (to NT).

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摘要：

基于记忆-表观遗传学特征，即由于参与认知功能基因的沉默，可导致记忆丧失的可能性。实验假设含有高蛋氨酸和低维生素的饮食可以通过增加全局DNA甲基化而导致记忆障碍，这一过程中沉默的netrin-1基因编码参与了神经发生、轴突导向和维持突触可塑性的糖蛋白。实验给予野生型（C57BL / 6J）小鼠喂食含有过量蛋氨酸（1.2％），低叶酸（0.08mg / kg）和低维生素B6（0.01mg / kg）和B12（10.4mg / kg）的饮食6周。每周以被动回避测试小鼠的长期记忆功能，确定了从喂食第4周开始的长期记忆丧失，同时观察到脑％5-甲基胞嘧啶的增加。甲基化敏感限制酶-PCR分析显示，上述饲料喂养的小鼠显示netrin-1蛋白表达减少和netrin-1基因启动子甲基化增加。高分辨率熔解和测序分析验证了netrin-1基因甲基化的增加。这些结果表明，富含蛋氨酸、低叶酸和低维生素B6 / B12的饮食可以诱导学习和记忆缺陷；由于netrin-1超甲基化致表达降低可能与记忆丧失有关。

orcid: 0000-0003-0856-7637 (Anuradha Kalani)
           0000-0001-6752-2688 (Pankaj Chaturvedi)

关键词: 阿尔茨海默病, 表观遗传学, 记忆, 蛋氨酸, 5-甲基胞嘧啶, 甲基化, netrin-1, 神经再生

Abstract:

Memory-epigenetics which is the loss of memory due to epigenetic modifications can be due to the silencing of genes involved in cognitive functions and this is the basis of the current study. We hypothesize that a diet containing high methionine and low vitamins can lead to memory impairment by increasing global DNA methylation and therefore, silencing the netrin-1 gene, which encodes the glycoprotein involved in neurogenesis, axonal guidance and maintenance of the synaptic plasticity. Wild type (C57BL/6J) mice were fed with a diet containing excess methionine (1.2%), low-folate (0.08 mg/kg), vitamin B6 (0.01 mg/kg), and B12 (10.4 mg/kg) for 6 weeks. Mice were examined weekly for the long-term memory function, using a passive avoidance test, which determined loss of fear-motivated long-term memory starting from the fourth week of diet. Similarly, an increase in brain %5-methyl cytosine was observed starting from the 4th week of diet in mice. Mice fed with a high methionine, low folate and vitamins containing diet showed a decrease in netrin-1 protein expression and an increase in netrin-1 gene promotor methylation, as determined by methylation-sensitive restriction enzyme-polymerase chain reaction analysis. The increase in methylation of netrin-1 gene was validated by high-resolution melting and sequencing analysis. Furthermore, the association of netrin-1 with memory was established by administering netrin that considerably restored long-term fear motivated memory. Taken together, these results suggest that a diet rich in methionine and lacking in folate and vitamin B6/B12 can induce defects in learning and memory. Furthermore, the data indicates that decrease in netrin-1 expression due to hyper-methylation of its gene can be associated with memory loss. The animal procedures were approved by the Institutional Animal Care and Use Committee, University of Louisville, USA (No. A3586-01) on February 2, 2018.

Key words: Alzheimer’s disease, epigenetics, memory, methionine, 5-methylcytosine, methylation, netrin-1