Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase 1 glycogen synthase kinase 3 beta in brain

According to the amyloid hypothesis for the pathogenesis of Alzheimer disease, beta-amyloid peptide (beta A) directly affects neurons, leading to neurodegeneration and tau phosphorylation, In rat hippocampal culture, beta A exposure activates tau protein kinase I/glycogen synthase kinase 3 beta (TPKI/GSK-3 beta), which phosphorylates tau protein into Alzheimer disease-like forms, resulting in neuronal death, To elucidate the mechanism of beta A-induced neuronal death, we searched for substrates of TPKI/GSK-3 beta in a two-hybrid system and identified pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA In mitochondria. PDH was phosphorylated and inactivated by TPKI/GSK-3 beta in vitro and also In beta A-treated hippocampal cultures, resulting in mitochondrial dysfunction, which would contribute to neuronal death, In cholinergic neurons, beta A impaired acetylcholine synthesis without affecting choline acetyltransferase activity, which suggests that PDH is inactivated by beta A-induced TPKI/GSK-3 beta. Thus, TPKI/GSK-3 beta regulates PDH and participates in energy metabolism and acetylcholine synthesis, These results suggest that TPKI/GSK-3 beta plays a key role in the pathogenesis of Alzheimer disease.