GSK-3 inhibition by adenoviral FRAT1 overexpression is neuroprotective andinduces Tau dephosphorylation and beta-catenin stabilisation without elevation of glycogen synthase activity

Glycogen synthase kinase 3 (GSK-3) has previously been shown to play an imp ortant role in the regulation of apoptosis. However, the nature of GSK-3 ef fector pathways that are relevant to neuroprotection remains poorly defined . Here, we have compared neuroprotection resulting from modulation of GSK-3 activity in PC12 cells using either selective small molecule ATP-competiti ve GSK-3 inhibitors (SB-216763 and SB-415286), or adenovirus overexpressing frequently rearranged in advanced T-cell lymphomas I (FRAT1), a protein pr oposed as a negative regulator of GSK-3 activity towards Axin and beta -cat enin. Our data demonstrate that cellular overexpression of FRAT1 is suffici ent to confer neuroprotection and correlates with inhibition of GSK-3 activ ity towards Tau and beta -catenin, but not modulation of glycogen synthase (GS) activity. By comparison, treatment with SB-216763 and SB-415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK-3 activity towards GS in addition to Tau and beta -catenin. (C) 2001 F ederation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.