Sodium butyrate induces aberrant tau phosphorylation and programmed cell death in human neuroblastoma cells

Paired helical filaments, one of the major hallmarks of Alzheimer's disease brains at autopsy, consist mainly of aberrantly phosphorylated tau. This aberrant tau phosphorylation can be induced in the human neuroblastoma cell line TR14 by a hyperstimulating mixture, consisting of nerve growth factor (NGF), db-cAMP, gangliosides and sodium butyrate (NaBut) [20,23]. Evidence is presented that exposing these cells to increasing concentrations of NaBut alone in the 0.5-2 mM dose-range is sufficient to induce aberrant tau phosphorylation within 24 h, measured by AT-8 immunocytochemistry and Western blotting. This process is associated with increased morphological differentiation. Furthermore, the aberrant tau phosphorylation is followed by neurotoxicity. This neurotoxicity has features of programmed cell death, such as fragmentation on a DNA agarose gel, fragmented nuclei and chromatin condensation and inhibition by the protein synthesis inhibitor cycloheximide. The mechanism by which NaBut induces these modified tau proteins and neurotoxicity are largely unknown but the data suggest an involvement of cytoskeletal proteins.