PHYSIOLOGY AND PATHOLOGY OF TAU-PROTEIN KINASES IN RELATION TO ALZHEIMERS-DISEASE

Alzheimer's disease (AD) is characterized by neuronal cell death and t wo kinds of deposits, neurofibrillary tangles (NFT) and senile plaques . The main component of NFT is paired helical filaments (PHF), which m ainly consist of hyperphosphorylated tau protein. Tau protein kinases I and II were found as candidate enzymes responsible for hyperphosphor ylation of tau to induce the formation of PHF. Since prior phosphoryla tion of tau by TPKII strongly enhanced the action of TPKI, it was thou ght that TPKII was involved in the formation of PHF-tau in concert wit h TPKI. After cloning, TPKI was found to be identical with glycogen sy nthase kinase 3 beta (GSK3 beta), while TPKII consists of a novel 23 k Da protein activator and a catalytic subunit that is identical with cy clin-dependent kinase 5 (CDK5). The phosphorylation sites on tau by TP KI and TPKII could account for the most, but not all, of the major pho sphorylation sites of fetal tau and PHF-tau. An antibody for a site sp ecifically phosphorylated by TPKI (Ser413) could identify all three ne urofibrillary lesions in the AD brain, and double staining for either TPKI or TPKII and NFT in the brain of Down's syndrome patients clearly demonstrated that TPKI and TPKII are both associated with NFT in vivo , suggesting that the level of TPKI or TPKII is elevated in AD brain b y some mechanism. On the other hand, the levels of both TPKs change de velopmentally, being high in the neonatal period when the phosphorylat ion of fetal tau proceeds actively, suggesting that the TPKI/TPKII coo perative system has an important physiological role in the formation o f neural networks. In AD brain, aberrant accumulation of amyloid-beta protein (A beta) occurs ahead of the accumulation of PHF in NFT. When a primary culture of embryonic rat hippocampus was treated with 20 mu M A beta, induction of TPKI, extensive phosphorylation of tau and then programmed cell death were observed, indicating that TPKI induced by A beta phosphorylates tau, followed by disruption of axonal transporta tion and finally cell death. By using a yeast two hybrid system, TPKI was found to interact with pyruvate dehydrogenase (PDH), which is a ke y enzyme in the glycolytic pathway. PDH was phosphorylated in vitro by TPKI to reduce the activity converting pyruvate into acetyl-CoA, whic h is required for acetylcholine synthesis. In a primary culture of rat hippocampal cells treated with A beta, PDH was inactivated in inverse relation to the activation of TPKI, resulting in accumulation of pyru vate or lactate, energy failure induced by the disturbance of glucose metabolism, and a shortage of acetylcholine owing to deficiency of ace tyl-CoA, all of which are characteristic of AD brain. In cholinergic n eurons such as those of the septum, non-aggregated A beta, specificall y A beta (1-42), not A beta (1-40), caused a shortage of acetylcholine by activation of TPKI and inactivation of PDH without cell death.