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
目的通过系统评价和实验验证,探讨微小RNA(miR)-15b-3p与卵巢储备功能减退(DOR)发生发展的关系。方法计算机检索PubMed、Cochrane Library、Embase、Web of Science、万方、中国知网、中国生物医学文献数据库,获取各数据库建库至2024年1...目的通过系统评价和实验验证,探讨微小RNA(miR)-15b-3p与卵巢储备功能减退(DOR)发生发展的关系。方法计算机检索PubMed、Cochrane Library、Embase、Web of Science、万方、中国知网、中国生物医学文献数据库,获取各数据库建库至2024年11月27日miRNA与DOR相关文献,根据纳入与排除标准筛选文献后,对纳入文献进行数据提取及质量评价,通过汇总、筛选、分析获得与DOR发生相关的miRNA。随后选取2024年3月至2024年12月在佛山复星禅诚医院中医妇科就诊的DOR患者和正常卵巢储备功能(NOR)患者为研究对象,检测患者血浆miR-15b-3p表达水平。结果共获得miRNA与DOR相关文献1626篇,最终纳入文献8篇,共涉及研究对象125人,其中实验组共62人,对照组共63人。8篇纳入文献共涉及10个独立研究、5种样本类型,结果共鉴定出94个miRNA至少在两项实验中差异表达。纳入文献的纽卡斯尔-渥太华量表(NOS)平均得分7.75分。临床检测结果显示,14位DOR患者和35位NOR患者血浆样本比较,DOR组患者血浆miR-15b-3p表达水平明显降低(P<0.001)。结论miR-221-3p、miR-483-3p、miR-126-5p、miR-15b-3p、miR-140-3p等miRNA在不同地区、样本来源的DOR患者中均差异表达,其中miR-15b-3p与DOR的发生发展密切相关,可能成为DOR早期检测和靶向治疗的潜在靶点。展开更多
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.
文摘目的通过系统评价和实验验证,探讨微小RNA(miR)-15b-3p与卵巢储备功能减退(DOR)发生发展的关系。方法计算机检索PubMed、Cochrane Library、Embase、Web of Science、万方、中国知网、中国生物医学文献数据库,获取各数据库建库至2024年11月27日miRNA与DOR相关文献,根据纳入与排除标准筛选文献后,对纳入文献进行数据提取及质量评价,通过汇总、筛选、分析获得与DOR发生相关的miRNA。随后选取2024年3月至2024年12月在佛山复星禅诚医院中医妇科就诊的DOR患者和正常卵巢储备功能(NOR)患者为研究对象,检测患者血浆miR-15b-3p表达水平。结果共获得miRNA与DOR相关文献1626篇,最终纳入文献8篇,共涉及研究对象125人,其中实验组共62人,对照组共63人。8篇纳入文献共涉及10个独立研究、5种样本类型,结果共鉴定出94个miRNA至少在两项实验中差异表达。纳入文献的纽卡斯尔-渥太华量表(NOS)平均得分7.75分。临床检测结果显示,14位DOR患者和35位NOR患者血浆样本比较,DOR组患者血浆miR-15b-3p表达水平明显降低(P<0.001)。结论miR-221-3p、miR-483-3p、miR-126-5p、miR-15b-3p、miR-140-3p等miRNA在不同地区、样本来源的DOR患者中均差异表达,其中miR-15b-3p与DOR的发生发展密切相关,可能成为DOR早期检测和靶向治疗的潜在靶点。
