POSSIBLE ROLE OF TAU-PROTEIN KINASES IN PATHOGENESIS OF ALZHEIMERS-DISEASE

Tau protein kinases (TPK) I and II were isolated as candidate enzymes responsible for the hyperphosphorylation observed in PHF-tau. Four pho sphorylation sites of tau were identified for each kinase, accounting for most, but not all, of the major phosphorylation sites of PHF-tau. Immunostaining with anti-TPKI antibody indicated that this Ginase is u p-regulated in AD brain. such up-regulation of TPKI and phosphorylatio n of tau were reproduced by treating cultured hippocampal cells with a myloid beta (A beta) protein. In addition, we found that TPKI can phos phorylate and inactivate pyruvate dehydrogenase (PDH), which is expect ed to result in depletion of acetyl-CoA, a key substrate of acetyl cho line synthesis. Indeed, when septum cells were treated with A beta, th e level of acetyl choline decreased dramatically. (C) 1998 Elsevier Sc ience Inc.