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 diseaseOA
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.
Li Zeng;Kaiyue Zhao;Jianghong Liu;Mimin Liu;Zhongdi Cai;Ting Sun;Zhuorong Li;Rui Liu
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,ChinaInstitute 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,ChinaDepartment of Neurology,Xuanwu Hospital,Capital Medical University,Beijing,ChinaInstitute 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,ChinaInstitute 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,ChinaInstitute 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,ChinaInstitute 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,ChinaInstitute 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,China
医药卫生
Alzheimer''s diseaseamyloid-beta peptide accumulationcognitive dysfunctioncompetitive endogenous RNAglycogen synthase kinase 3betalncRNA growth arrest-specific 5microRNA-23b-3pneuronal apoptosisphosphatase and tensin homologue deleted on chromosome 10tau phosphorylation
《Neural Regeneration Research》 2026 (1)
P.392-405,14
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)。
评论