BETA-AMYLOID-INDUCED NEUROTOXICITY OF A HYBRID SEPTAL CELL-LINE ASSOCIATED WITH INCREASED TAU-PHOSPHORYLATION AND EXPRESSION OF BETA-AMYLOID PRECURSOR PROTEIN

Recent evidence suggests that beta-amyloid peptide (beta-AP) may induc e tau protein phosphorylation, resulting in loss of microtubule bindin g capacity and formation of paired helical filaments. The mechanism by which beta-AP increases tau phosphorylation, however, is unclear, Usi ng a hybrid septal cell line, SN56, we demonstrate that aggregated bet a-AP(1-40) treatment caused cell injury. Accompanying the cell injury, the levels of phosphorylated tau as well as total tau were enhanced a s detected immunochemically by AT8, PHF-1, Tau-1, and Tau-5 antibodies . Alkaline phosphatase treatment abolished AT8 and PHF-1 immunoreactiv ity, confirming that the tau phosphorylation sites were at least al Se r(199/202) and Ser(396). In association with the increase in tau phosp horylation, the immunoreactivity of cell-associated and secreted beta- amyloid precursor protein (beta-APP) was markedly elevated. Applicatio n of antisense oligonucleotide to beta-APP reduced expression of beta- APP and immunoreactivity of phosphorylated tau. Control peptide beta-A P(1-28) did not produce significant effects on tau phosphorylation, al though it slightly increased cell-associated beta-APP. These results s uggest that beta-AP(1-40)-induced tau phosphorylation may be associate d with increased beta-APP expression in degenerated neurons.