title: Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β.
abstract: Abnormally hyperphosphorylated tau is often caused by tau kinases, such as GSK3β and Cdk5. Such occurrence leads to neurofibrillary tangle formation and neuronal degeneration in tauopathy, including Alzheimer's disease (AD). However, little is known about the signaling cascade underlying the pathologic phosphorylation of tau by Aβ(42). In this study, we show that adenylate kinase 1 (AK1) is a novel regulator of abnormal tau phosphorylation. AK1 expression is markedly increased in the brains of AD patients and AD model mice and is significantly induced by Aβ(42) in the primary neurons. Ectopic expression of AK1 alone augments the pathologic phosphorylation of tau at PHF1, CP13 and AT180 epitopes and enhances the formation of tau aggregates. Inversely, downregulation of AK1 alleviates Aβ(42)-induced hyperphosphorylation of tau. AK1 plays a role in Aβ(42)-induced impairment of AMPK activity and GSK3β activation in the primary neurons. Pharmacologic studies show that treatment with an AMPK inhibitor activates GSK3β, and a GSK3β inhibitor attenuates AK1-mediated tau phosphorylation. In a Drosophila model of human tauopathy, the retinal expression of human AK1 severely exacerbates rough eye phenotype and increases abnormal tau phosphorylation. Further, neural expression of AK1 reduces the lifespan of tau transgenic files. Taken together, these observations indicate that the neuronal expression of AK1 is induced by Aβ(42) to increase abnormal tau phosphorylation via AMPK-GSK3β and contributes to tau-mediated neurodegeneration, providing a new upstream modulator of GSK3β in the pathologic phosphorylation of tau.
authors.affiliation: Global Research Laboratory, School of Biological Science/Bio-MAX Institute, Seoul National University, Seoul, South Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Park
authors.forename: Tae-In
authors.initials: TI
authors.lastname: Kam
authors.forename: Youngdoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Choi
authors.forename: Youngdae
authors.initials: Y
authors.lastname: Gwon
authors.forename: Changsoo
authors.initials: C
authors.lastname: Kim
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D049452:Green Fluorescent Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; C110939:adenylate kinase 1