Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β

Hyejin Park, Tae In Kam, Youngdoo Kim, Hyunwoo Choi, Youngdae Gwon, Changsoo Kim, Jae Young Koh, Yong Keun Jung

Research output: Contribution to journalArticle

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 Aβ42. 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 Aβ42 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 Aβ42-induced hyperphosphorylation of tau. AK1 plays a role in Aβ42-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 Aβ42 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.

Original languageEnglish (US)
Article numberdds100
Pages (from-to)2725-2737
Number of pages13
JournalHuman molecular genetics
Volume21
Issue number12
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Park, H., Kam, T. I., Kim, Y., Choi, H., Gwon, Y., Kim, C., Koh, J. Y., & Jung, Y. K. (2012). Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β. Human molecular genetics, 21(12), 2725-2737. [dds100]. https://doi.org/10.1093/hmg/dds100