Objective Mir-153 can negatively regulate the expression of APP and APLP2 protein，the crucial Alzheimer’s disease related genes， and consequently lower the level of their intracellular degradation fragment ( intracellular domains，ICDs) ． Considering the transcriptional activity and pro-apoptotic role of ICDs，the aim of this study was to explore the effect of mir-153 on the expression of GSK-3β，the downstream signaling molecule of the two target genes，and on the ability of cells against damage stress to further identify the role of mir-153 in Alzheimer’s disease．Methods A stably transfected cell line over-expressing mir-153 was developed and mir-153 transgenic mice were generated． Western blot was used to detect the expression of phosphorylated GSK-3β，Tau and their total protein in the cells and mice． The mir-153 stably transfected cells were treated with Aβ42 peptide and H2O2，respectively，to determine the changes of cell viability by MTS and analyze the cell apoptosis by flow cytometry． Results The expression of phosphorylated GSK-3β and it’s total protein were decreased and the phosphorylation of Tau was reduced in the mir-153 stably transfected cells． The expression of phosphorylated GSK-3β and it’s total protein were down-regulated and the level of phosphorylated Tau and its total protein were not significantly changed in the brain of mir-153 transgenic mice． Under the treatment of Aβ42 peptide and H2O2，the viability of mir-153 stably transfected cells were clearly decreased and the apoptosis level of the cells was increased． Conclusion Mir-153 can negatively regulate the expression of GSK-3β，the downstream signaling molecule of its target genes． Over-expressed mir-153 lowers the cellular anti-injury ability．