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
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 olig...
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| Format: | Article |
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Wolters Kluwer Medknow Publications
2026-01-01
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| Series: | Neural Regeneration Research |
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| Online Access: | https://journals.lww.com/10.4103/NRR.NRR-D-23-01273 |
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| author | Li Zeng Kaiyue Zhao Jianghong Liu Mimin Liu Zhongdi Cai Ting Sun Zhuorong Li Rui Liu |
| author_facet | Li Zeng Kaiyue Zhao Jianghong Liu Mimin Liu Zhongdi Cai Ting Sun Zhuorong Li Rui Liu |
| author_sort | Li Zeng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c337f78de84c4418b0991e50843eee67 |
| institution | DOAJ |
| issn | 1673-5374 1876-7958 |
| language | English |
| publishDate | 2026-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
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| series | Neural Regeneration Research |
| spelling | doaj-art-c337f78de84c4418b0991e50843eee672025-08-20T03:07:54ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53741876-79582026-01-0121139240510.4103/NRR.NRR-D-23-01273Long noncoding RNA GAS5 acts as a competitive endogenous RNA to regulate GSK-3β and PTEN expression by sponging miR-23b-3p in Alzheimer’s diseaseLi ZengKaiyue ZhaoJianghong LiuMimin LiuZhongdi CaiTing SunZhuorong LiRui LiuLong 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.https://journals.lww.com/10.4103/NRR.NRR-D-23-01273alzheimer’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 |
| spellingShingle | Li Zeng Kaiyue Zhao Jianghong Liu Mimin Liu Zhongdi Cai Ting Sun Zhuorong Li Rui Liu 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 Neural Regeneration Research alzheimer’s disease amyloid-beta peptide accumulation cognitive dysfunction competitive endogenous rna glycogen synthase kinase 3beta lncrna growth arrest-specific 5 microrna-23b-3p neuronal apoptosis phosphatase and tensin homologue deleted on chromosome 10 tau phosphorylation |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | alzheimer’s disease amyloid-beta peptide accumulation cognitive dysfunction competitive endogenous rna glycogen synthase kinase 3beta lncrna growth arrest-specific 5 microrna-23b-3p neuronal apoptosis phosphatase and tensin homologue deleted on chromosome 10 tau phosphorylation |
| url | https://journals.lww.com/10.4103/NRR.NRR-D-23-01273 |
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