Abstract: This study aimed at exploring the molecular mechanism of fibroin peptide in preventing the Aβ_25-35-induced neuronal damages in SH-SY5Y cells. MTT was used to detect the effect of fibroin peptide on the changes of the Aβ_25-35-induced injuries in SH-SY5Y cells; Western blot was employed to detect the effect of fibroin peptide on the changes of the Aβ_25-35-induced hyperphosphorylation of Tau in SH-SY5Y cells; DCFH-DA probe method was used to detect the effect of fibroin peptide on the Aβ-induced production of intracellular reactive oxygen species(ROS)in SH-SY5Y cells. The results indicated that fibroin peptide could improve the activity of the PP2A and inhibit the activity of GSK-3β to decrease the hyperphosphorylation of Tau induced by Aβ_25-35. Fibroin peptide could significantly prevent the Aβ_25-35-induced neuronal damages and multisite Tau hyperphosphorylation. In addition, fibroin peptide could also reduce oxidative damage to protect neurons by significantly decreasing the Aβ_25-35-induced production of intracellular ROS.