OBJECTIVE: To explore the mechanism of ubiquitin-proteasome pathway(UPP) in the degradation of hyperphosphorylated tau protein in aluminum-induced mouse neuroblastoma N2 a cells. METHODS: N2 a cells in logarithmic growth period were randomly divided into control group and MG132 group. Cells in control group were exposed to concentrations of 0 or 1 mmol/L aluminum chloride for 24 hours. Cells in MG132 group were pretreated with MG132 at a concentration of 5 μmol/L for 6 hours, then exposed to concentrations of 0 or 1 mmol/L aluminum chloride for 24 hours. After exposure, the cells were collected. Western blotting was used to detect the relative expression of tau-5, P-tau181, P-tau231, P-tau262, P-tau396, heat shock protein 70(Hsp70) and carboxyl terminus of the Hsp70-interacting protein(CHIP). The ubiquitin relative expression was detected by enzyme-linked immunosorbent assay. RESULTS: The results of factorial analysis showed that the relative expression of tau-5, P-tau231, P-tau262, P-tau396, CHIP, Hsp70 and ubiquitin in N2 a cells were statistically significant in the main effect and interaction effect of aluminum chloride and MG132 treatment(P<0.05). Both in the control group and MG132 group, the relative expression of tau-5, P-tau231, P-tau262, P-tau396, CHIP, Hsp70 and ubiquitin in N2 a cells exposed to 1 mmol/L aluminum chloride increased(P<0.05) when compared with the N2 a cells without exposed to aluminum chloride. No matter aluminum chloride exposed or not, the relative expression of tau-5, P-tau231, P-tau262, P-tau396, CHIP, Hsp70 and ubiquitin in N2 a cells of MG132 group was higher than that of control group(P<0.05). CONCLUSION: UPP is involved in the regulation of hyperphosphorylated tau protein by proteasome degradation in aluminum-induced N2 a cells. UPP mainly regulates P-tau231, P-tau262, and P-tau396 sites. CHIP and Hsp70 played an important role in the UPP pathway.