Zeng Li, Zhao Kaiyue, Liu Jianghong, Liu Mimin, Cai Zhongdi, Sun Ting, Li Zhuorong, Liu Rui
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, China.
Neural Regen Res. 2024 Jul 29;21(1):392-405. doi: 10.4103/NRR.NRR-D-23-01273.
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.
长链非编码RNA和微小RNA是与阿尔茨海默病相关的调控性非编码RNA，但长链非编码RNA相关的竞争性内源RNA的作用尚未完全阐明。长链非编码RNA生长停滞特异性5（GAS5）是5'-末端寡嘧啶基因家族的成员，可能参与神经疾病，但它在阿尔茨海默病中的作用仍不清楚。本研究旨在探讨GAS5的功能，并构建一个包含潜在靶点的GAS5相关竞争性内源RNA网络。RNA测序结果显示，GAS5在五只家族性阿尔茨海默病（5×FAD）小鼠、APPswe/PSEN1dE9（APP/PS1）小鼠、阿尔茨海默病相关的APPswe细胞以及阿尔茨海默病患者的血清中上调。靶向过表达和沉默的功能实验表明，GAS5在认知功能障碍和多种阿尔茨海默病相关病理过程中发挥作用，包括tau蛋白过度磷酸化、淀粉样β蛋白积累和神经元凋亡。机制研究表明，GAS5通过竞争结合微小RNA-23b-3p（miR-23b-3p）作为内源性海绵，以依赖于AGO2诱导的RNA沉默复合体（RISC）的方式调节其靶点糖原合酶激酶3β（GSK-3β）和10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）的表达。GAS5通过前馈PTEN/蛋白激酶B（Akt）/GSK-3β连锁抑制miR-23b-3p介导的GSK-3β和PTEN级联反应。此外，GAS5/miR-23b-3p/GSK-3β/PTEN通路的恢复减轻了体内阿尔茨海默病样症状，表现为空间认知、神经元变性、淀粉样β蛋白负荷和tau蛋白磷酸化的改善。总之，这些发现表明GAS5促进阿尔茨海默病的发病机制。本研究确立了GAS5/miR-23b-3p/GSK-3β/PTEN通路在多种病理过程中的功能汇聚，提示其为阿尔茨海默病的一个候选治疗靶点。
