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.