Tau protein is hyperphosphorylated in a site-specific manner in apoptotic neuronal PC12 cells

Alterations in the status of microtubules contribute to the cytoskeletal re arrangements that occur during apoptosis. The microtubule-associated protei n tau regulates microtubule dynamics and thus is likely to play an importan t role in the cytoskeletal changes that occur in apoptotic cells. Previousl y, we demonstrated that the phosphorylation of tau at the Tau-1 epitope was increased during neuronal PC12 cell apoptosis, and further that the microt ubule binding of tau from apoptotic cells was significantly impaired becaus e of altered phosphorylation. The fact that the microtubule-binding capacit y of tau from apoptotic cells was reduced to similar to 30% of control valu es indicated that sites in addition to those within the Tau-1 epitope were hyperphosphorylated during apoptosis. In this study using a combination of immunological and biochemical approaches, numerous sites were found to be h yperphosphorylated on tau isolated from apoptotic cells. Further, during ap optosis, the activities of cell division control protein kinase (cdc2) and cyclin-dependent kinase 5 (cdk5) were selectively and significantly increas ed. The association of these two protein kinases with tau was also increase d during apoptosis. These findings are intriguing because many of the sites found to be hyperphosphorylated on tau during apoptosis are also hyperphos phorylated on tau from Alzheimer's disease brain. Likewise, there are data indicating that in Alzheimer's disease the activities of cdc2 and cdk5 are also increased.