靶向微RNA的阿尔茨海默病防治研究进展  

A state-of-the-art review on miRNA in prevention and treatment of Alzheimer’s disease

作　　者：郭锡汉[1] GUO Xihan(School of Life Science,Yunnan Normal University,Engineering Research Center,Sustainable Development and Utilization of Biomass Energy of the Ministry of Education,Kunming 650500,China)

机构地区：[1]云南师范大学生命科学学院,生物能源持续开发与利用教育部工程研究中心,云南昆明650500

出　　处：《浙江大学学报（医学版）》2023年第4期485-498,共14页Journal of Zhejiang University(Medical Sciences)

基　　金：国家自然科学基金(32260148,31900410);云南省基础研究计划(202001AU070055,202101AT070112);云南师范大学优秀青年学者项目。

摘　　要：阿尔茨海默病(AD)是一种多因异质性疾病。微RNA(miRNA)是一类长度为19~22个核苷酸的短链非编码RNA,可特异性地从转录后水平调控靶基因的表达。AD患者的脑组织、脑脊液甚至血液中miRNA表达谱与健康者存在明显差异,实验研究证实miRNA表达的改变能通过多种途径驱动AD的发生及发展。因此,靶向调控miRNA以纠正AD发生发展过程中关键基因的异常表达,有望成为新兴的AD防治手段。以啮齿类动物AD模型为代表的研究表明,靶向miRNA可以阻断Aβ生成或降低其毒性、抑制τ蛋白的产生及其过度磷酸化、防止神经元凋亡和促进神经发生、维持突触和钙的稳态、舒缓小胶质细胞介导的神经炎症。此外,动物模型和人群研究表明,采用miRNA细胞治疗和生活方式干预可在预防AD发生发展过程中发挥重要作用。本文以啮齿类动物AD模型和人群干预实验为重点,主要围绕近五年的研究成果,从多个层面系统性阐述了miRNA在AD防治中的作用、分子机制和应用前景,以及开展相关临床试验所面临的机遇和挑战。Alzheimer’s disease(AD)is a multifactorial and heterogenic disorder.MiRNA is a class of non-coding RNAs with 19-22 nucleotides in length that can regulate the expression of target genes in the post-transcriptional level.It has been found that the miRNAome in AD patients is significantly altered in brain tissues,cerebrospinal fluid and blood circulation,as compared to healthy subjects.Experimental studies have suggested that expression changes in miRNA could drive AD onset and development via different mechanisms.Therefore,targeting miRNA expression to regulate the key genes involved in AD progression is anticipated to be a promising approach for AD prevention and treatment.Rodent AD models have demonstrated that targeting miRNAs could block biogenesis and toxicity of amyloidβ,inhibit the production and hyperphosphorylation ofτprotein,prevent neuronal apoptosis and promote neurogenesis,maintain neural synaptic and calcium homeostasis,as well as mitigate neuroinflammation mediated by microglia.In addition,animal and human studies support the view that miRNAs are critical players contributing to the beneficial effects of cell therapy and lifestyle intervention to AD.This article reviews the most recent advances in the roles,mechanisms and applications of targeting miRNA in AD prevention and treatment based on rodent AD models and human intervention studies.The potential opportunities and challenges in clinical application of targeting miRNA for AD patients are also discussed.

关 键 词：阿尔茨海默病 微RNA Β淀粉样蛋白 Τ蛋白 神经炎症 神经发生 突触稳定性 综述 

分 类 号：R741.02[医药卫生—神经病学与精神病学]