Long noncoding RNA GAS5 acts as a competitive endogenous RNA to regulate GSK-3β and PTEN expression by sponging miR-23b-3p in Alzheimer's disease
Li Zeng1
Kaiyue Zhao1
Jianghong Liu2
Mimin Liu1
Zhongdi Cai1
Ting Sun1
Zhuorong Li1
Rui Liu1
1.Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China;State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Medicinal Biotechnology,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China2.Department of Neurology,Xuanwu Hospital,Capital Medical University,Beijing,China
摘要：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(5xFAD)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.
机标关键词：alzheimerexpressionptenlongactscompetitivediseaseendogenous
论文发表日期：2026-01-30
在线出版日期：2025-12-11（本平台首次上网日期，不代表文献的发表时间）
页数：14( 392-405 )
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