DEVELOPMENTAL REGULATION AND PKC DEPENDENCE OF ALZHEIMERS-TYPE TAU-PHOSPHORYLATION IN CULTURED FETAL-RAT HIPPOCAMPAL-NEURONS

Attempts to describe a mechanism of neurofibrillary tangle formation o ften focus on site specific phosphorylations of tau protein. These hav e typically been described in both Alzheimer's disease and developing brains. Therefore, study of the developmental regulation of Alzheimer epitope tau phosphorylations may help explain their persistence or rec urrence during Alzheimer's disease. Using fetal rat hippocampal cultur es, we report a spatial and temporal expression of tau phosphorylation during neuronal differentiation. We have examined phosphorylation at the epitopes recognized by monoclonal antibodies, PHF-1 and Tau 1. Tau was highly phosphorylated at the PHF-1 epitope at all culture ages ex amined using both immunohistochemical staining and Western blots. Tau was heavily phosphorylated at the Tau 1 epitope only in older cultures . The populations of tau recognized by the two antibodies also exhibit ed different solubilities, suggesting different microtubule binding be haviors: tau phosphorylated at PHF-1 was retained in axons following s olubilization whereas Tau 1 immunoreactive tau was not retained in any cell compartment. Finally, in this culture system, maintenance of pho sphorylation at the PHF-1 epitope, but not the Tau 1 epitope, required protein kinase C activity. These results indicate unique regulatory m echanisms and roles for each of these phosphorylated tau epitopes. (C) 1998 Elsevier Science B.V.