Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation
| Autor: | M-L, Selenica, H S, Jensen, A K, Larsen, M L, Pedersen, L, Helboe, M, Leist, J, Lotharius |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Aging
Indoles Blotting Western tau Proteins macromolecular substances phosphorylated tau Cell Line Maleimides Small Molecule Libraries Glycogen Synthase Kinase 3 ddc:570 Animals Humans Immunoprecipitation Enzyme Inhibitors Phosphorylation Rats Wistar AR-A014418 CHIR98014 Brain Chemistry Neurons Tissue Extracts Brain Indirubin-3'-monoxime Immunohistochemistry Research Papers Recombinant Proteins Rats Thiazoles Animals Newborn Female SB216763 Lithium Chloride |
| Popis: | Background and purpose: Glycogen synthase kinase-3 (GSK-3) affects neuropathological events associated with Alzheimers disease (AD) such as hyperphosphorylation of the protein, tau. GSK-3beta expression, enzyme activity and tau phosphorylated at AD-relevant epitopes are elevated in juvenile rodent brains. Here, we assess five GSK-3beta inhibitors and lithium in lowering phosphorylated tau (p-tau) and GSK-3beta 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-3beta enzyme activities in the same tissues. Effects of GSK inhibitors on p-tau, GSK-3beta 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-3beta enzyme activity assays. The inhibitory effect on GSK-3beta activity ex vivo correlated with protection against cell death and decrease of p-tau- in LUHMES cells, using low microM inhibitor concentrations.Conclusions and implications: Selective small-molecule inhibitors of GSK-3 reduce tau phosphorylation in vivo. These findings corroborate earlier suggestions that GSK-3beta may be an attractive target for disease-modification in AD and related conditions where tau phosphorylation is believed to contribute to disease pathogenesis. |
| Databáze: | OpenAIRE |
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