| Autor: |
Maj-Linda Bardyl Selenica, Anna Kirstine Larsen, M. L. Pedersen, Julie Lotharius, Marcel Leist, Lone Helboe, Henning S. Jensen |
| Rok vydání: |
2007 |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology. 152:959-979 |
| ISSN: |
0007-1188 |
| DOI: |
10.1038/sj.bjp.0707471 |
| 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-3b expression, enzyme activity and tau phosphorylated at AD-relevant epitopes are elevated in juvenile rodent brains. Here, we assess five GSK-3b inhibitors and lithium in lowering phosphorylated tau (p-tau) and GSK-3b 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-3b enzyme activities in the same tissues. Effects of GSK inhibitors on p-tau, GSK-3b 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 0 -monoxime were ineffective in either brain region. Inhibition of p-tau in brain required several-fold higher levels of GSK inhibitors than the IC50 values obtained in recombinant or cell-based GSK-3b enzyme activity assays. The inhibitory effect on GSK-3b activity ex vivo correlated with protection against cell death and decrease of p-tau- in LUHMES cells, using low mM inhibitor concentrations. Conclusions and Implications: Selective small-molecule inhibitors of GSK-3 reduce tau phosphorylation in vivo. These findings corroborate earlier suggestions that GSK-3b 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 |
| Externí odkaz: |
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