Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3β mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing

Cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3 beta(GSK3 beta) have been implicated in pathogenic processes associated with Alzheimer's disease because both kinases regulate tau hyperphosphorylation and enhance amyloid precursor protein (APP) processing leading to an increase in amyloid beta(A beta) production. Here we show that young p25 overexpressing mice have enhanced cdk5 activity but reduced GSK3 beta activity attributable to phosphorylation at the inhibitory GSK3 beta-serine 9 (GSK3 beta-S9) site. Phosphorylation at this site was mediated by enhanced activity of the neuregulin receptor complex, ErbB, and activation of the downstream phosphatidylinositol 3 kinase/Akt pathway. Young p25 mice had elevated A beta peptide levels, but phospho-tau levels were decreased overall. Thus, cdk5 appears to play a dominant role in the regulation of amyloidogenic APP processing, whereas GSK3 beta plays a dominant role in overall tau phosphorylation. In older mice, GSK3 beta inhibitory phosphorylation at S9 was reduced relative to young mice. A beta peptide levels were still elevated but phospho-tau levels were either unchanged or showed a trend to increase, suggesting that GSK3 beta activity increases with aging. Inhibition of cdk5 by a specific inhibitor reduced cdk5 activity in p25 mice, leading to reduced A beta production in both young and old mice. However, in young mice, cdk5 inhibition reversed GSK3 beta inhibition, leading to an increase in overall tau phosphorylation. When cdk5 inhibitor was administered to very old, nontransgenic mice, inhibition of cdk5 reduced A beta levels, and phospho-tau levels showed a trend to increase. Thus, cdk5 inhibitors may not be effective in targeting tau phosphorylation in the elderly.