Abnormal phosphorylation of microtubule associated protein τ is one of the major mechanism in Alzheimer neurofibrillary degeneration. It was found that casein kinase-1 (CK-1), cyclic AMP-dependent protein kinase (PKA) and glycogen synthase kinase-3 (GSK-3) differentially phosphorylate humanτ(τ3L) and thus inhibit its biological activity. Morever, the phosphorylation and inhibition of this activity of τ by GSK-3 is significantly increased if τ is prephosphorylated by PKA. Under this condition, only neglectable microtubles could be seen by electron microscopy. The data suggest that a synergistic role of PKA and GSK-3 might be involved in abnormal phosphorlation and functional inhibition of τ in Alzheimer disease.