Yang Guoshuai, Song Yanmin, Zhou Xiaoyan, Deng Yidong, Liu Tao, Weng Guohu, Yu Dan, Pan Suyue
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
Mol Med Rep. 2015 Jul;12(1):1435-42. doi: 10.3892/mmr.2015.3531. Epub 2015 Mar 23.
Alzheimer's disease (AD), the most common form of dementia in the aged population, presents an increasing clinical challenge in terms of diagnosis and treatment. Neurodegeneration is one of the hallmarks of AD, which consequently induces cognitive impairment. Brain-derived neurotrophic factor (BDNF), a neuroprotective factor, has been implicated in neuronal survival and proliferation. The epigenetic mechanism of BDNF methylation may be responsible for the reduced expression of BDNF in patients with AD. DNA methyltransferase may contribute to the methylation of BDNF, which is involved in neuroprotection in AD. In addition, epigenetic modifications, including a combination of microRNAs (miRNAs/miRs) and DNA methylation, have been suggested as regulatory mechanisms in the control of neuronal survival. In the present study, the expression of miR-29c was determined in the cerebrospinal fluid (CSF) of patients with AD and of healthy control individuals. A marked decrease in the expression of miR-29c was observed in the AD group compared with the normal control group, accompanied by a decreased in the expression of BDNF. Additionally, a significant increase in the expression of DNA methyltransferase 3 (DNMT3) was observed in the CSF from the patients with AD. Correlation analysis revealed that the expression of miR-29c was positively correlated with BDNF and negatively correlated with DNMT3 protein in the CSF of patients with AD. In addition, the regulatory association between miR-29c, DNMT3 and BDNF were also examined in vitro. It was demonstrated that miR-29c directly targeted DNMT3 and contributed to neuronal proliferation by regulating the expression of BDNF, at least partially, through enhancing the activity of the tyrosine receptor kinase B/extracellular signal-regulated kinase signaling pathway. In conclusion, the present study suggested that miR-29c may be a promising potential therapeutic target in the treatment of AD.
阿尔茨海默病（AD）是老年人群中最常见的痴呆形式，在诊断和治疗方面带来了日益严峻的临床挑战。神经退行性变是AD的特征之一，进而导致认知障碍。脑源性神经营养因子（BDNF）是一种神经保护因子，与神经元的存活和增殖有关。BDNF甲基化的表观遗传机制可能是AD患者中BDNF表达降低的原因。DNA甲基转移酶可能导致BDNF的甲基化，这与AD中的神经保护有关。此外，包括微小RNA（miRNA/miR）和DNA甲基化组合在内的表观遗传修饰已被认为是控制神经元存活的调节机制。在本研究中，测定了AD患者和健康对照个体脑脊液（CSF）中miR-29c的表达。与正常对照组相比，AD组中miR-29c的表达明显降低，同时BDNF的表达也降低。此外，在AD患者的CSF中观察到DNA甲基转移酶3（DNMT3）的表达显著增加。相关性分析显示，AD患者CSF中miR-29c的表达与BDNF呈正相关，与DNMT3蛋白呈负相关。此外，还在体外研究了miR-29c、DNMT3和BDNF之间的调控关系。结果表明，miR-29c直接靶向DNMT3，并至少部分地通过增强酪氨酸受体激酶B/细胞外信号调节激酶信号通路的活性来调节BDNF的表达，从而促进神经元增殖。总之，本研究表明miR-29c可能是治疗AD的一个有前景的潜在治疗靶点。
