表观遗传修饰调控阿尔茨海默病的研究进展

Research Progress of Epigenetic Modification in The Regulation of Alzheimer’s Disease

阿尔茨海默病(Alzheimer’s disease,AD)是一种临床上常见的以进行性认知功能障碍和记忆减退为主要特征的神经退行性疾病。近些年研究发现,表观遗传修饰如DNA修饰、组蛋白修饰、RNA修饰及非编码RNA在Aβ沉积、Tau蛋白过度磷酸化、神经再生、突触可塑性和认知功能中发挥不同程度的调控作用,进而改善或加剧AD病理进程。临床数据表明表观遗传修饰的改变与AD风险呈显著相关性,运用药物、物理刺激、si RNA等干预手段在AD动物模型中改变表观遗传修饰水平可改善AD病理和认知能力。本文综述了不同的表观遗传修饰在AD中的调控作用,为进一步理解AD的表观遗传学机制及通过干预表观遗传修饰改善或治疗AD的可行性提供理论依据。

Alzheimer’s disease(AD)is a clinically common neurodegenerative disease characterized by progressive cognitive dysfunction and memory loss.In recent years,studies have found that various epigenetic modifications such as DNA modification,histone modification,RNA modification and non-coding RNA play pivotal roles in the regulation of Aβdeposition,hyperphosphorylated Tau proteins,nerve regeneration,synaptic plasticity and cognitive function,thereby improving or aggravating the pathological process of AD.Decreasing 5-methylcytosine of PSEN1 and BACE1 genes may cause Aβproduction via promotion of PSEN1 and BACE1expression.Increasing DNA modifications of 5-hydroxymethylcytosine by Tet1/Tet2/Tet3 protein can regulate proliferation,differentiation and function of neurons,neural stem cells,and neural progenitor cells.Moreover,increasing histone methylation(H3K9me2 and H3K4me3)and demethylation(H3K27me3)catalyzed by histone methyltransferase and demethylase respectively can decrease neuronal differentiation and cognition.Low acetylation levels of histones maintained by the suppression of histone acetylases and activation of histone deacetylases(HDAC2,HDAC3 and HDAC6)can be contributed to inducing cognitive impairment.Furthermore,N6-methyladenosine(m6A)RNA modification catalyzed by the RNA methyltransferases Mettl3 and Mettl14(writers),removed by the demethylases FTO(erasers),and interacted with m6A-binding proteins YTHDF1 and YTHDF(readers)is involved in synaptic plasticity,neuronal apoptosis and synaptic transmission.In addition,low expression of mi R-29,mi R-31 and mi R-101 causes Aβdeposition by improving BACE1 and APP levels.Either declining mi R-34a,mi R-219 or raising mi R-128a,mi R-125b,and mi R-124 can lead to high levels of Tau protein and Tau hyperphosphorylation.The up-regulation of mi R-137 and mi R-142 can reduce synaptic plasticity and stimulate neuroinflammation,respectively.Overexpression of lnc RNA BACE1-AS and BC200 can promote Aβdeposition by boosting BACE1 expression,while enhancing BDNF-AS and GDNFOS result in neurodevelopment disorder by inhibiting BDNF and GDNF expression.Clinical data shows that changes in epigenetic modifications are significantly correlated with AD risk.The use of drugs,physical stimulation,si RNA and other interventions to change the level of epigenetic modifications in AD animal models can ameliorate AD pathology and cognitive impairment.Our paper reviews the regulatory effects of various epigenetic modifications in AD and in the hope of providing a theoretical basis for further understanding of the epigenetic mechanism in AD and a feasible interventions for preventing or treating AD via alteration epigenetic modifications.