Recent evidence suggests that beta-amyloid peptide (beta-AP) may induce tau protein phosphorylation, resulting in loss of microtubule binding capacity and formation of paired helical filaments. The mechanism by which beta-AP increases tau phosphorylation, however, is unclear. Using a hybrid septal cell line, SN56, we demonstrate that aggregated beta-AP(1-40) treatment caused cell injury. Accompanying the cell injury, the levels of phosphorylated tau as well as total tau were enhanced as detected immunochemically by AT8, PHF-1, Tau-1, and Tau-5 antibodies. Alkaline phosphatase treatment abolished AT8 and PHF-1 immunoreactivity, confirming that the tau phosphorylation sites were at least at Ser(199/202) and Ser396. In association with the increase in tau phosphorylation, the immunoreactivity of cell-associated and secreted beta-amyloid precursor protein (beta-APP) was markedly elevated. Application of antisense oligonucleotide to beta-APP reduced expression of beta-APP and immunoreactivity of phosphorylated tau. Control peptide beta-AP(1-28) did not produce significant effects on tau phosphorylation, although it slightly increased cell-associated beta-APP. These results suggest that betaAP(1-40)-induced tau phosphorylation may be associated with increased beta-APP expression in degenerated neurons.