Objective：This study aims to investigate the effect of integrated stress response inhibitor（ISRIB）in apoptosis and endoplasmic reticulum stress of SH-SY5Y cells induced by amyloid β-amyloid protein1-42（Aβ1-42）and to clarify its mechanism. Methods：SH-SY5Y cells were divided into normal control group，Aβ group，ISRIB group and ISRIB+Aβ group. The survival rate of cells in each group was detected by MTT colorimetric assay. Western blotting was used to examine the expression of endoplasmic reticulum stress marker glucose-regulated protein 78（GRP78）and activation of protein kinase R-like ER kinase（PERK）-eukaryotic initiation factor 2α（eIF2α）-activation transcription factor 4（ATF4）signaling pathway，together with C/EBP homologous protein（CHOP）. Meanwhile，apoptosis-related proteins were also detected，including Bcl-2、Bax and cleaved-caspase3. Results：Compared with Aβ group，ISRIB significantly increased the survival rate of SH-SY5Y cells（P < 0.01），significantly decreased the activation of p-PERK（P < 0.01），p-eIF2α（P<0.05），ATF4（P < 0.05）and CHOP（P < 0.05），increased Bcl-2/Bax level（P < 0.05）and decreased cleaved-casepase3 expression（P < 0.01）. Conclusion：ISRIB could inhibit the apoptosis of SH-SY5Y cells induced by Aβ1-42，and its mechanism is related to the inhibiting the activation of eIF2α pathway and apoptotic signaling pathway induced by ERS.