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, leadi ng to neurodegeneration and tau phosphorylation, In rat hippocampal cu lture, beta A exposure activates tau protein kinase I/glycogen synthas e kinase 3 beta (TPKI/GSK-3 beta), which phosphorylates tau protein in to Alzheimer disease-like forms, resulting in neuronal death, To eluci date the mechanism of beta A-induced neuronal death, we searched for s ubstrates of TPKI/GSK-3 beta in a two-hybrid system and identified pyr uvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA In mi tochondria. 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 withou t affecting choline acetyltransferase activity, which suggests that PD H is inactivated by beta A-induced TPKI/GSK-3 beta. Thus, TPKI/GSK-3 b eta regulates PDH and participates in energy metabolism and acetylchol ine synthesis, These results suggest that TPKI/GSK-3 beta plays a key role in the pathogenesis of Alzheimer disease.