Akt-activated GSK3β inhibitory peptide effectively blocks tau phosphorylation

Abstract

Tau hyperphosphorylation and accumulation in neurofibrillary tangles are closely associated with cognitive deficits in Alzheimer's disease (AD). Abnormal overexpression of GSK3β has been implicated in tau hyperphosphorylation, thus many GSK3β inhibitors have been developed as drug candidates for AD. However, the potent GSK3β inhibitors are prone to show side effects because they can interfere with basal GSK3β function. We have recently reported that the specific motifs in the Wnt coreceptor LRP6 are able to directly inhibit GSK3β when phosphorylated, an thus a novel GSK3β inhibitory peptide (GIP) that can be activated by Akt, was generated by combining the LRP6 motif and an Akt target sequence. In the present study, we tested the effects of a novel GIP on modulating tau phosphorylation and tauopathy. The GSK3β-inhibitory action of GIP was tested ex vivo using hippocampal brain tissue. Human neuroblastoma SH-SY5Y cells were used to determine the protective effects of GIP against Aβ-induced death and tau phosphorylation. We used 3xTg-AD mice to verify the effect of GIP on the tau hyperphosphorylation and Aβ plaques in vivo. GIP effectively blocked GSK3 β -induced tau phosphorylation in hippocampal homogenate. In addition, the GIP fused with a cell permeable sequence attenuated Aβ-induced tau phosphorylation and cell death in human neuroblastoma cells. Interestingly, high Akt activation was observed particularly in the hippocampus assuming that GIP can be activated to inhibit GSK3 β. T he designed GIP significantly reduced tau phosphorylation in the hippocampus of 3 ' Tg-AD mice without affecting levels of Aβ plaques. In conclusion, the current findings provide a novel concept for the drug development targeting tau hyperphosphorylation in AD, and GIP may have potential as a therapeutic drug in tauopathies.