Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation

M. L. Selenica, H. S. Jensen, A. K. Larsen, M. L. Pedersen, L. Helboe, M. Leist, J. Lotharius

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


Background and purpose: Glycogen synthase kinase-3 (GSK-3) affects neuropathological events associated with Alzheimeŕs disease (AD) such as hyperphosphorylation of the protein, tau. GSK-3β expression, enzyme activity and tau phosphorylated at AD-relevant epitopes are elevated in juvenile rodent brains. Here, we assess five GSK-3β inhibitors and lithium in lowering phosphorylated tau (p-tau) and GSK-3β enzyme activity levels in 12-day old postnatal rats. Experimental approach: Brain levels of inhibitors following treatment in vivo were optimized based on pharmacokinetic data. At optimal doses, p-tau (Ser 396) levels in brain tissue was measured by immunoblotting and correlated with GSK-3β enzyme activities in the same tissues. Effects of GSK inhibitors on p-tau, GSK-3β activities and cell death were measured in a human neuronal cell line (LUHMES). Key results: Lithium and CHIR98014 reduced tau phosphorylation (Ser 396) in the cortex and hippocampus of postnatal rats, while Alsterpaullone and SB216763 were effective only in hippocampus. AR-A014418 and Indirubin-3′-monoxime were ineffective in either brain region. Inhibition of p-tau in brain required several-fold higher levels of GSK inhibitors than the IC 50 values obtained in recombinant or cell-based GSK-3β enzyme activity assays. The inhibitory effect on GSK-3β activity ex vivo correlated with protection against cell death and decrease of p-tau- in LUHMES cells, using low μM inhibitor concentrations. Conclusions and Implications: Selective small-molecule inhibitors of GSK-3 reduce tau phosphorylation in vivo. These findings corroborate earlier suggestions that GSK-3β may be an attractive target for disease-modification in AD and related conditions where tau phosphorylation is believed to contribute to disease pathogenesis.

Original languageEnglish
Pages (from-to)959-979
Number of pages21
JournalBritish Journal of Pharmacology
Issue number6
StatePublished - Nov 2007


  • AR-A014418
  • Alsterpaullone
  • CHIR98014
  • Indirubin-3′- monoxime
  • LiCl
  • Phosphorylated tau
  • SB216763

ASJC Scopus subject areas

  • Pharmacology


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