Tau phosphorylation at serine 396 and serine 404 by human recombinant tau protein kinase II inhibits tan's ability to promote microtubule assembly

In Alzheimer's disease, hyperphosphorylated tau is an integral part of the neurofibrillary tangles that form within neuronal cell bodies and fails to promote microtubule assembly, Dysregulation of the brain-specific tau prote in kinase II is reported to play an important role in the pathogenesis of A lzheimer's disease (Patrick, G. N., Zukerberg, L., Nikolic, M., De La Monte , S., Dikkes, P., and Tsai, L.-H, (1999) Nature 402, 615-622), We report he re that in vitro phosphorylation of human tau by human recombinant tau prot ein kinase II severely inhibits the ability of tau to promote microtubule a ssembly as monitored by tubulin polymerization. The ultrastructure of tau-m ediated polymerized tubulin was visualized by electron microscopy and compa red with phosphorylated tau, Consistent with the observed slower kinetics o f tubulin polymerization, phosphorylated tau is compromised in its ability to generate microtubules. Moreover, me show that phosphorylation of microtu bule-associated tau results in tau's dissociation from the microtubules and tubulin depolymerization, Mutational studies with human tau indicate that phosphorylation by tau protein kinase II at serine 396 and serine 404 is pr imarily responsible for the functional loss of tau-mediated tubulin polymer ization. These in vitro results suggest a possible role for tau protein kin ase II-mediated tau phosphorylation in initiating the destabilization of mi crotubules.