Tau protein, a neuronal microtubule-associated protein is phosphorylated on several sites when extracted from brain tissue and is a substrate for many protein kinases in vitro. In Alzheimer's disease it becomes hyperphosphorylated, notably at Ser-Pro or Thr-Pro motifs, and forms the paired helical filaments (PHFs). The increased phosphorylation can be detected by several antibodies raised against Alzheimer tau. We show here that a similar type of phosphorylation can be observed in cells of neuronal origin during mitosis. Murine neuroblastoma cells (N2a) were stably transfected with htau40, the largest of the six human tau isoforms in the brain. We used several antibodies reporting on the state of phosphorylation of tau (Tau-1, AT8, AT180, PHF-1, and T46) and the antibody MPM-2 that recognizes phosphorylated mitotic proteins. The results show that tau is in a state of low phosphorylation in interphase cells, whereas during mitosis it becomes highly phosphorylated. This behavior was also found for endogenous tau protein in human neuroblastoma cells (LAN-5). The similarity between tau phosphorylation in dividing neuronal cells and Alzheimer degenerating neurons may indicate that aging neurons exposed to inappropriate signals respond by an attempt to activate their machinery for regeneration.