title: [Involvement of tau protein kinase in amyloid-beta-induced neurodegeneration].
abstract: Histopathological features of Alzheimer's disease (AD) include extracellular deposits of amyloid beta (A beta) fibrils in the cores of senile plaques, intracellular neurofibrillary tangles (NFT) which are composed of paired helical filaments (PHF), and neuronal cell loss. The main component of PHF is highly phosphorylated tau protein. We identified a protein kinase converting normal tau into a PHF-like state. The kinase is tau protein kinase (TPK) I/glycogen synthase kinase (GSK)-3 beta. Using a neuronal cell culture system as an AD model, it was recognized that TPK I/GSK-3 beta plays a central role in AD pathology. We hypothesize that A beta-induced neuronal cell death occurs by the following mechanism. A beta inactivates PI3-kinase and activates TPK I/GSK-3 beta, which in turn phosphorylates and inactivates both tau and pyruvate dehydrogenase (PDH). After the ability of tau to promote microtubule assembly is diminished by phosphorylation, soluble tau molecules aggregate into PHF by an unknown mechanism. Destabilization of microtubule arrays causes inhibition of axonal transport and accumulation of amyloid precursor protein (APP). Phosphorylation of PDH inhibits the reaction converting pyruvate to acetyl-CoA, resulting in inhibition of energy metabolism and a decrease in acetylcholine, both of which are also characteristics of AD. These changes may lead to neuronal cell death.
authors.affiliation: Mitsubishi Kasei Institute of Life Sciences, Machida.
authors.forename: K
authors.initials: K
authors.lastname: Ishiguro
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death; D038362:Glycogen Synthase Kinase 3; D009410:Nerve Degeneration; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase