Abstract: AimTo investigate the inhibition of amyloid β-protein 42 (Aβ₄₂) production in M146L cells by γ-schisandrin. MethodsM146L cells which can produce considerable Aβ₄₂in vitro were treated with ₄₂-schisandrin (1.67, 5.00 and 15.00 μg·mL^-1), β-secretase inhibitor (S4562, 100.00 μg·mL^-1) and ₄₂-secretase inhibitor (S2188, 13.68 μg·mL^-1), separately. Cell counting kit-8 (CCK-8) was used to assess cell viability. Enzyme-linked immunosorbent assay (ELISA) was carried out to determine the amount of Aβ₄₂. Western blotting was used to examine C99, an intermediary product of APP cleaved by β-secretase. β-Secretase and ₄₂-secretase activities were assayed by commercial kits. Results The CCK-8 assay indicated that different concentrations of γ-schisandrin had no neurotoxicity on the cultured M146L. And the ELISA test showed that the amount of Aβ₄₂secreted by M146L cells treated with γ-schisandrin (5.00 and 15.00 μg·mL^-1) decreased obviously as compared with solvent control. The results of Western blotting test indicated that there was no change of C99 contents and β-secretase activity in γ-schisandrin treated cells, while γ-secretase activity decreased obviously. Conclusionγ-Schisandrin inhibited production of Aβ₄₂ in M146L cells through inhibiting γ-secretase.