This study aims to investigate the effects of resveratrol (Res) on cell apoptosis through endoplasmic reticulum stress (ERS) pathway and phosphorylation of glycogen synthase kinase-3β（GSK-3β） and Tau protein.Primary cultured neurons were used in vitro to establish an ERS model induced by tunicamycin (TM).Western blot analysis was performed to detect the levels of the endoplasmic reticulum molecular chaperone protein glucose-regulated protein 78（GRP78）,unfolded protein response related inositol-requiring enzyme 1α（IRE1α） phosphorylation and spliced form of X-box binding protein 1s(XBP1s） expression,phosphorylation of GSK-3β and Tau protein.Biochemical methods were used to analyze the activity of Caspase-12 and Caspase-3,as well as the level of cell apoptosis.The results indicated that TM induces endoplasmic reticulum stress,leading to increasing in neuronal GSK-3β activation and Tau protein phosphorylation (P<0.01),as well as neuronal apoptosis through the endoplasmic reticulum pathway(P<0.05).Compared with the TM model group,like the inhibitor of endoplasmic reticulum stress 4-phenylbutyric acid,the Res protection group significantly reduced the expression of GRP78,phosphorylated IRE1α at Ser724,and XBP1s (P<0.01).Res reduced TM-induced the activity of both Caspase-12 and Caspase-3 and neuronal apoptosis(P<0.01).Res also inhibited TM-induced the phosphorylation levels of GSK-3β at Ser9 and Tau protein at Ser396 (P<0.01).In conclusion,Res could reduce TM-induced endoplasmic reticulum stress on IRE1α-XBP1 pathway,the activity of GSK-3β,and the phosphorylation level of Tau protein,and weaken the cascade reaction of neuronal apoptosis through the endoplasmic reticulum pathway.