| First Author | Park H | Year | 2012 |
| Journal | Hum Mol Genet | Volume | 21 |
| Issue | 12 | Pages | 2725-37 |
| PubMed ID | 22419736 | Mgi Jnum | J:184464 |
| Mgi Id | MGI:5424070 | Doi | 10.1093/hmg/dds100 |
| Citation | Park H, et al. (2012) Neuropathogenic role of adenylate kinase-1 in Abeta-mediated tau phosphorylation via AMPK and GSK3beta. Hum Mol Genet 21(12):2725-37 |
| abstractText | Abnormally hyperphosphorylated tau is often caused by tau kinases, such as GSK3beta 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 Abeta(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 Abeta(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 Abeta(42)-induced hyperphosphorylation of tau. AK1 plays a role in Abeta(42)-induced impairment of AMPK activity and GSK3beta activation in the primary neurons. Pharmacologic studies show that treatment with an AMPK inhibitor activates GSK3beta, and a GSK3beta 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 Abeta(42) to increase abnormal tau phosphorylation via AMPK-GSK3beta and contributes to tau-mediated neurodegeneration, providing a new upstream modulator of GSK3beta in the pathologic phosphorylation of tau. |
