Possible Role of Tau Protein Kinases in Pathogenesis of Alzheimer’s Disease

Tau protein kinases (TPK) I and II were isolated as candidate enzymes responsible for the hyperphosphorylation observed in PHF-τ. Four phosphorylation sites of tau were identified for each kinase, accounting for most, but not all, of the major phosphorylation sites of PHF-τ. Immunostaining with anti-TPKI antibody indicated that this kinase is up-regulated in AD brain. Such up-regulation of TPKI and phosphorylation of tau were reproduced by treating cultured hippocampal cells with amyloid β (Aβ) protein. In addition, we found that TPKI can phosphorylate and inactivate pyruvate dehydrogenase (PDH), which is expected to result in depletion of acetyl-CoA, a key substrate of acetyl choline synthesis. Indeed, when septum cells were treated with Aβ, the level of acetyl choline decreased dramatically.