RAPID ALZHEIMER-LIKE PHOSPHORYLATION OF TAU BY THE SYNERGISTIC ACTIONS OF NON-PROLINE-DEPENDENT PROTEIN-KINASES AND GSK-3

Tau protein from Alzheimer disease (AD) brain is phosphorylated at ele ven Ser/Thr-Pro and nine Ser/Thr-X sites. The former sites are phospho rylated by proline-dependent protein kinases (PDPKs), the latter by no n-PDPKs. The identities of both the PDPKs and non-PDPKs involved in AD tau hyperphosphorylation are still to be established. In this study w e have analyzed the interactions between a PDPK (GSK-3) and several no n-PDPKs (A-kinase, C-kinase, CK-1, CaM kinase II) in the phosphorylati on of one isoform (tau 39) of human tau. We found that the rate of pho sphorylation of tau 39 by GSK-3 was increased several-fold if tau were first prephosphorylated by the non-PDPKs. Further, several Alzheimer- like epitopes in tau can be induced only slowly after phosphorylation of tau by GSK-3 alone. After a prephosphorylation of tau by the non-PD PKs, however, the rate of induction of these epitopes by GSK-3 is incr eased several-fold. These results suggest that one role of non-PDPK-ca talyzed phosphorylation is the modulation of PDPK-catalyzed phosphoryl ation of tan in AD brain.