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 di sease brains at autopsy, consist mainly of aberrantly phosphorylated t au. This aberrant tau phosphorylation can be induced in the human neur oblastoma 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 inc reasing concentrations of NaBut alone in the 0.5-2 mM dose-range is su fficient to induce aberrant tan phosphorylation within 24 h, measured by AT-8 immunocytochemistry and Western blotting. This process is asso ciated with increased morphological differentiation. Furthermore, the aberrant tau phosphorylation is followed by neurotoxicity. This neurot oxicity has features of programmed cell death, such as fragmentation o n a DNA agarose gel, fragmented nuclei and chromatin condensation and inhibition by the protein synthesis inhibitor cycloheximide. The mecha nism by which NaBut induces these modified tau proteins and neurotoxic ity are largely unknown but the data suggest an involvement of cytoske letal proteins.