| First Author | Wang Y | Year | 2015 |
| Journal | Neurobiol Aging | Volume | 36 |
| Issue | 1 | Pages | 188-200 |
| PubMed ID | 25219467 | Mgi Jnum | J:218431 |
| Mgi Id | MGI:5617455 | Doi | 10.1016/j.neurobiolaging.2014.07.035 |
| Citation | Wang Y, et al. (2015) Cross talk between PI3K-AKT-GSK-3beta and PP2A pathways determines tau hyperphosphorylation. Neurobiol Aging 36(1):188-200 |
| abstractText | Glycogen synthase kinase-3beta (GSK-3beta) and protein phosphatase 2A (PP2A) are the important enzymes controlling tau hyperphosphorylation. The relationship between these two enzymes and its impact on tau hyperphosphorylation are not well understood. In the present study, we determined the cross talk between PI3K-AKT-GSK-3beta and PP2A pathways and found that the former regulated the methylation of PP2Ac via GSK-3beta. Upregulation of GSK-3beta led to an increase in the methylation and activity of PP2Ac through suppression of protein phosphatase methylesterase-1 expression and phosphorylation of leucine carboxyl methyltransferase 1. PP2A also regulated GSK-3beta phosphorylation. Downregulation of PP2A enhanced Ser9 phosphorylation of GSK-3beta and inhibited its kinase activity. Thus, GSK-3beta and PP2A regulate each other and control tau phosphorylation both directly and indirectly through each other. Reduction of tau phosphorylation by inhibition of GSK-3beta may be more than offset by inhibition of PP2A through a shift in phosphatase methylesterase-1/leucine carboxyl methyltransferase 1 balance; PP2A regulates phosphorylation of tau at Ser262/356, a required site for tau pathology. These findings suggest targeting PP2A rather than GSK-3beta to inhibit tau pathology. |
