《生命科学》 2022, 34(9): 1116-1125

miRNAs靶向调控Aβ生成的机制研究进展

杞燕梅¹ , 苏建培² , 汪　旭¹ , 郭锡汉^1,*

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， 昆明 650500 ²昆明市第二人民医院老年一科，昆明 650500

摘　要：

miRNAs 是一类内源性的、长度为19~24 nt 的非编码RNA，可特异性地靶向基因并在转录后调控基因的表达，在发育和组织内稳态中发挥重要的调节作用。近期，越来越多的证据表明部分miRNAs 的异常表达在衰老和阿尔茨海默病(Alzheimer’s disease, AD) 等神经退行性疾病中起关键作用。作为AD 患者最显著的病理特征和AD 发生发展的主导因素之一，β 淀粉样蛋白(β-amyloid protein, Aβ) 的大量产生与miRNAs 的表达异常息息相关。Aβ 由淀粉样前体蛋白(APP) 经β- 分泌酶(BACE1) 和γ- 分泌酶( 其催化亚基为PSEN1) 剪切而成。此外，α- 分泌酶(ADAM10) 可与β- 分泌酶竞争性剪切APP，从而抑制Aβ 的产生。本文就靶向调控APP、BACE1、PSEN1 和ADAM10 基因表达的miRNAs 及其作用机制的研究进展进行综述，为今后探索AD 的临床诊断手段和潜在的治疗靶点提供理论依据。

通讯作者：郭锡汉 , Email:guo_xihan@163.com

Targeted regulation of Aβ generation by miRNAs: the current advances

QI Yan-Mei¹ , SU Jian-Pei² , WANG Xu¹ , GUO Xi-Han^1,*

¹School of Life Science, Engineering Research Center of Sustainable Development and Utilization of Biomass Energy, Ministry of Education, Yunnan Normal University, Kunming 650500, China ²Department of Geriatrics, Kunming Second People’s Hospital, Kunming 650500, China

Abstract:

The microRNAs (miRNAs), a class of endogenous non-coding RNAs with a length of 19-24 nt, can specifically bind to the mRNA of target genes and regulate the expression of target genes at the post-transcriptional level. Through fine tuning gene expression, miRNAs play critical roles in physiological development and tissue homeostasis. miRNAs expression significantly alters during cellular aging and neurodegeneration. Recently, increasing evidence has revealed some of the de-expressed miRNAs exert essential roles in aging and neurodegenerative diseases such as Alzheimer’s disease (AD). As the most significant pathological feature of AD brain and a risk factor for AD initiation and development, increased production of β-amyloid protein (Aβ) is tightly associated with miRNA de-expression. Aβ is produced from a stepwise cleavage of the amyloid precursor protein (APP), which is mediated by β-secretase (BACE1) and γ-secretase (its catalytic subunit PSEN1). In addition, α-secretase (ADAM10) can compete with BACE1 to cleave APP, thereby reducing Aβ production in this pathway. Herein, we summarize the miRNAs that can specifically target and regulate the expression of APP, BACE1, PSEN1 and ADAM10, and discuss the underlying molecular mechanisms. Understanding this biological process may provide a framework to explore the potential clinical diagnostic methods and therapeutic targets for AD.

Communication Author：GUO Xi-Han , Email:guo_xihan@163.com