Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathologica...Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathological characteristics and molecular pathways associated with its progression.Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease.These non-coding RNAs regulate several biological processes critical to the advancement of the disease,offering promising potential as therapeutic targets and diagnostic biomarkers.Therefore,this review aims to investigate the underlying mechanisms of Alzheimer's disease onset,with a particular focus on microRNAs,long non-coding RNAs,and circular RNAs associated with the disease.The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs.It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease,as well as how these noncoding RNAs influence the disease's progression by regulating gene expression and protein functions.For example,miR-9 targets the UBE4B gene,promoting autophagy-mediated degradation of Tau protein,thereby reducing Tau accumulation and delaying Alzheimer's disease progression.Conversely,the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA,promoting the generation of amyloid-βand accelerating Alzheimer's disease development.Additionally,circular RNAs play significant roles in regulating neuroinflammatory responses.By integrating insights from these regulatory mechanisms,there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease.This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs,potentially paving the way for early detection and novel treatment strategies.展开更多
背景:阿尔茨海默病病因多样且发病机制复杂,至今尚未完全阐明。近年来,非编码RNA被证实在调控β-淀粉样蛋白异常沉积、Tau蛋白过度磷酸化、神经炎症激活、线粒体功能障碍及突触损伤等过程中发挥关键作用,为阐释疾病机制和药物研发提供...背景:阿尔茨海默病病因多样且发病机制复杂,至今尚未完全阐明。近年来,非编码RNA被证实在调控β-淀粉样蛋白异常沉积、Tau蛋白过度磷酸化、神经炎症激活、线粒体功能障碍及突触损伤等过程中发挥关键作用,为阐释疾病机制和药物研发提供了新视角。同时,中医药通过调控非编码RNA网络展现了多通路干预优势。目的:综述近年来调节性非编码RNA和转运RNA在阿尔茨海默病病理机制中的相关研究,总结中药单体、复方及针灸调控不同非编码RNA发挥抗阿尔茨海默病的现状,以期为今后阿尔茨海默病临床治疗策略优化及新型药物研发提供理论依据与方向参考。方法:以“非编码RNA、微小RNA、长链非编码RNA、环状RNA、转运RNA、阿尔茨海默病、中医药”为中文检索词,以“ncRNA,miRNA,lncRNA,circRNA,tRNA,Alzheimer’s disease,traditional Chinese Medicine”为英文检索词,检索中国知网和PubMed数据库2015年1月至2025年7月发表的相关文献,根据纳入及排除标准最终纳入101篇文献进行综述分析。结果与结论:①阿尔茨海默病的发生与发展源于一个多因素相互关联的病理网络,主要包括β-淀粉样蛋白沉积、Tau蛋白过度磷酸化、神经炎症激活、线粒体功能障碍、氧化应激、突触结构与功能异常以及钙稳态失衡等关键机制,这些因素之间亦可彼此交织、协同促进疾病进程;②多种调节性非编码RNA如微小RNA、长链非编码RNA、环状RNA以及管家非编码RNA中的转运RNA可通过不同层面调控上述病理过程,进而影响疾病进展;③诸多中药单体活性成分如小檗碱、梓醇、三七总皂苷、人参皂苷Rg1、β-细辛醚、雷公藤内酯醇、丹参酮IIA;中药复方如安神定志方、调心方、补肾填髓方以及针刺和艾灸等中医疗法均能通过上调或下调特定非编码RNA的表达,干预阿尔茨海默病的多个病理环节,发挥神经保护作用,从而延缓疾病的发生与发展。展开更多
以高耐热性玉米品种郑单958、低耐热性玉米品种先玉335为试验材料,以正常生长条件为对照(CK),利用半自动伸缩高温棚进行花期高温胁迫(HT)处理,通过circRNA高通量测序筛选高温胁迫下不同玉米品种花粉中差异表达的环状RNA(circRNA),对其...以高耐热性玉米品种郑单958、低耐热性玉米品种先玉335为试验材料,以正常生长条件为对照(CK),利用半自动伸缩高温棚进行花期高温胁迫(HT)处理,通过circRNA高通量测序筛选高温胁迫下不同玉米品种花粉中差异表达的环状RNA(circRNA),对其来源基因进行GO和KEGG富集分析,并筛选具有miRNA结合位点的差异表达circRNA,预测其下游目的基因,分析玉米花粉中响应高温胁迫的潜在circRNA-miRNA-mRNA共表达调控网络,从多层面解析玉米花粉中调控高温胁迫的分子作用机制,为提高玉米品种的耐热性提供理论依据。结果表明,在郑单958、先玉335不同样本中共鉴定出1 843个不同的circRNA,它们在玉米染色体中的分布不同。每个circRNA所包含的外显子数目也不相同,其中,大多数(624个)circRNA只含有1个外显子。在郑单958花粉中共鉴定出1 563个circRNA,其中,CK958-1、CK958-2、CK958-3中分别鉴定出305、213、356个circRNA,HT958-1、HT958-2、HT958-3中分别鉴定出222、242、225个circRNA。在先玉335花粉中共鉴定出1 423个circRNA,其中,CK335-1、CK335-2、CK335-3中分别鉴定出272、188、229个circRNA,HT335-1、HT335-2、HT335-3中分别鉴定出259、237、238个circRNA。不同样本中占比最高的均为外显子circRNA。circRNA与其来源基因不是一一对应的关系,有748个circRNA来源基因通过反向剪接机制只形成1个circRNA,156个circRNA来源基因通过反向剪接机制各自形成2个circRNA。在郑单958高温胁迫花粉与对照花粉对比组(HT958 vs CK958)中共筛选到9个差异表达circRNA,其中2个circRNA呈上调表达,其来源基因显著富集到焦磷酸酶活性、核苷酸磷酸代谢过程、糖基磷脂酰肌醇(GPI)锚定代谢过程等17个GO条目,显著富集到GPI锚定生物合成、代谢途径等KEGG通路。在先玉335高温胁迫花粉与对照花粉对比组(HT335 vs CK335)中共筛选到1个差异表达circRNA,其来源基因没有显著富集到任何GO条目、KEGG通路。在郑单958高温胁迫花粉与先玉335高温胁迫花粉对比组(HT958 vs HT335)中共筛选到17个差异表达circRNA,其中6个circRNA呈上调表达,其来源基因显著富集到内质网系统、高尔基相关囊泡膜、膜蛋白水解等16个GO条目中,没有显著富集到任何KEGG代谢通路。5个circRNA具有miRNA结合位点,可以作为海绵岛吸附miRNA间接调控下游靶标基因的表达,构建了包括5个circRNA、5个不同家族miRNA、2个mRNA在内的circRNA-miRNA-mRNA共表达调控网络。筛选到了54个circRNA包含内部核糖体进入位点(IRES),可以翻译表达多肽或者蛋白质直接作用于靶标基因。展开更多
真核生物RNA聚合酶Ⅳ(polymerasesⅣ,PolⅣ)和Ⅴ(PolⅤ)是植物特有的RNA指导DNA甲基化(RNA-directed DNA methylation,RdDM)通路的核心酶,介导重要的表观遗传调控过程。当前分子生物学教材对其介绍明显不足,制约了学生对该领域的深入理...真核生物RNA聚合酶Ⅳ(polymerasesⅣ,PolⅣ)和Ⅴ(PolⅤ)是植物特有的RNA指导DNA甲基化(RNA-directed DNA methylation,RdDM)通路的核心酶,介导重要的表观遗传调控过程。当前分子生物学教材对其介绍明显不足,制约了学生对该领域的深入理解。本文基于RNA PolⅣ与RDR2协同组装、RNA PolⅤ转录停滞等最新结构生物学进展,系统阐述其亚基组成、结构特征与功能分工;进而依据建构主义及循证教学原则,提出以概念脚手架和科学叙事法更新教材内容,并引入可视化分析、角色模拟与案例研讨等教学方法,构建了面向知识-能力-素养协同培养的教学范式,为弥合学科前沿与课堂教学的差距提供系统解决方案,并为农林院校分子生物学课程改革与创新人才培养提供了可借鉴的范式。展开更多
Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The...Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.展开更多
文摘Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathological characteristics and molecular pathways associated with its progression.Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease.These non-coding RNAs regulate several biological processes critical to the advancement of the disease,offering promising potential as therapeutic targets and diagnostic biomarkers.Therefore,this review aims to investigate the underlying mechanisms of Alzheimer's disease onset,with a particular focus on microRNAs,long non-coding RNAs,and circular RNAs associated with the disease.The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs.It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease,as well as how these noncoding RNAs influence the disease's progression by regulating gene expression and protein functions.For example,miR-9 targets the UBE4B gene,promoting autophagy-mediated degradation of Tau protein,thereby reducing Tau accumulation and delaying Alzheimer's disease progression.Conversely,the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA,promoting the generation of amyloid-βand accelerating Alzheimer's disease development.Additionally,circular RNAs play significant roles in regulating neuroinflammatory responses.By integrating insights from these regulatory mechanisms,there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease.This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs,potentially paving the way for early detection and novel treatment strategies.
文摘背景:阿尔茨海默病病因多样且发病机制复杂,至今尚未完全阐明。近年来,非编码RNA被证实在调控β-淀粉样蛋白异常沉积、Tau蛋白过度磷酸化、神经炎症激活、线粒体功能障碍及突触损伤等过程中发挥关键作用,为阐释疾病机制和药物研发提供了新视角。同时,中医药通过调控非编码RNA网络展现了多通路干预优势。目的:综述近年来调节性非编码RNA和转运RNA在阿尔茨海默病病理机制中的相关研究,总结中药单体、复方及针灸调控不同非编码RNA发挥抗阿尔茨海默病的现状,以期为今后阿尔茨海默病临床治疗策略优化及新型药物研发提供理论依据与方向参考。方法:以“非编码RNA、微小RNA、长链非编码RNA、环状RNA、转运RNA、阿尔茨海默病、中医药”为中文检索词,以“ncRNA,miRNA,lncRNA,circRNA,tRNA,Alzheimer’s disease,traditional Chinese Medicine”为英文检索词,检索中国知网和PubMed数据库2015年1月至2025年7月发表的相关文献,根据纳入及排除标准最终纳入101篇文献进行综述分析。结果与结论:①阿尔茨海默病的发生与发展源于一个多因素相互关联的病理网络,主要包括β-淀粉样蛋白沉积、Tau蛋白过度磷酸化、神经炎症激活、线粒体功能障碍、氧化应激、突触结构与功能异常以及钙稳态失衡等关键机制,这些因素之间亦可彼此交织、协同促进疾病进程;②多种调节性非编码RNA如微小RNA、长链非编码RNA、环状RNA以及管家非编码RNA中的转运RNA可通过不同层面调控上述病理过程,进而影响疾病进展;③诸多中药单体活性成分如小檗碱、梓醇、三七总皂苷、人参皂苷Rg1、β-细辛醚、雷公藤内酯醇、丹参酮IIA;中药复方如安神定志方、调心方、补肾填髓方以及针刺和艾灸等中医疗法均能通过上调或下调特定非编码RNA的表达,干预阿尔茨海默病的多个病理环节,发挥神经保护作用,从而延缓疾病的发生与发展。
文摘以高耐热性玉米品种郑单958、低耐热性玉米品种先玉335为试验材料,以正常生长条件为对照(CK),利用半自动伸缩高温棚进行花期高温胁迫(HT)处理,通过circRNA高通量测序筛选高温胁迫下不同玉米品种花粉中差异表达的环状RNA(circRNA),对其来源基因进行GO和KEGG富集分析,并筛选具有miRNA结合位点的差异表达circRNA,预测其下游目的基因,分析玉米花粉中响应高温胁迫的潜在circRNA-miRNA-mRNA共表达调控网络,从多层面解析玉米花粉中调控高温胁迫的分子作用机制,为提高玉米品种的耐热性提供理论依据。结果表明,在郑单958、先玉335不同样本中共鉴定出1 843个不同的circRNA,它们在玉米染色体中的分布不同。每个circRNA所包含的外显子数目也不相同,其中,大多数(624个)circRNA只含有1个外显子。在郑单958花粉中共鉴定出1 563个circRNA,其中,CK958-1、CK958-2、CK958-3中分别鉴定出305、213、356个circRNA,HT958-1、HT958-2、HT958-3中分别鉴定出222、242、225个circRNA。在先玉335花粉中共鉴定出1 423个circRNA,其中,CK335-1、CK335-2、CK335-3中分别鉴定出272、188、229个circRNA,HT335-1、HT335-2、HT335-3中分别鉴定出259、237、238个circRNA。不同样本中占比最高的均为外显子circRNA。circRNA与其来源基因不是一一对应的关系,有748个circRNA来源基因通过反向剪接机制只形成1个circRNA,156个circRNA来源基因通过反向剪接机制各自形成2个circRNA。在郑单958高温胁迫花粉与对照花粉对比组(HT958 vs CK958)中共筛选到9个差异表达circRNA,其中2个circRNA呈上调表达,其来源基因显著富集到焦磷酸酶活性、核苷酸磷酸代谢过程、糖基磷脂酰肌醇(GPI)锚定代谢过程等17个GO条目,显著富集到GPI锚定生物合成、代谢途径等KEGG通路。在先玉335高温胁迫花粉与对照花粉对比组(HT335 vs CK335)中共筛选到1个差异表达circRNA,其来源基因没有显著富集到任何GO条目、KEGG通路。在郑单958高温胁迫花粉与先玉335高温胁迫花粉对比组(HT958 vs HT335)中共筛选到17个差异表达circRNA,其中6个circRNA呈上调表达,其来源基因显著富集到内质网系统、高尔基相关囊泡膜、膜蛋白水解等16个GO条目中,没有显著富集到任何KEGG代谢通路。5个circRNA具有miRNA结合位点,可以作为海绵岛吸附miRNA间接调控下游靶标基因的表达,构建了包括5个circRNA、5个不同家族miRNA、2个mRNA在内的circRNA-miRNA-mRNA共表达调控网络。筛选到了54个circRNA包含内部核糖体进入位点(IRES),可以翻译表达多肽或者蛋白质直接作用于靶标基因。
文摘真核生物RNA聚合酶Ⅳ(polymerasesⅣ,PolⅣ)和Ⅴ(PolⅤ)是植物特有的RNA指导DNA甲基化(RNA-directed DNA methylation,RdDM)通路的核心酶,介导重要的表观遗传调控过程。当前分子生物学教材对其介绍明显不足,制约了学生对该领域的深入理解。本文基于RNA PolⅣ与RDR2协同组装、RNA PolⅤ转录停滞等最新结构生物学进展,系统阐述其亚基组成、结构特征与功能分工;进而依据建构主义及循证教学原则,提出以概念脚手架和科学叙事法更新教材内容,并引入可视化分析、角色模拟与案例研讨等教学方法,构建了面向知识-能力-素养协同培养的教学范式,为弥合学科前沿与课堂教学的差距提供系统解决方案,并为农林院校分子生物学课程改革与创新人才培养提供了可借鉴的范式。
基金supported by the National Natural Science Foundation of China,Nos. 82173806 and U1803281Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science,Nos. 2021-I2M-1-030 and 2022-I2M-2-002Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-JKCS-08 (all to RL)。
文摘Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.
