KOPS - Das Institutionelle Repositorium der Universität Konstanz

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

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

Zitieren

Dateien zu dieser Ressource

Prüfsumme: MD5:550861d4ba1724cf4a06796510e41180

SELENICA, Maj-Linda, Henning S. JENSEN, Anna Kirstine LARSEN, M. L. PEDERSEN, Lone HELBOE, Marcel LEIST, Julie LOTHARIUS, 2007. Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation. In: British Journal of Pharmacology. 152(6), pp. 959-979. ISSN 0007-1188

@article{Selenica2007-11Effic-1262, title={Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation}, year={2007}, doi={10.1038/sj.bjp.0707471}, number={6}, volume={152}, issn={0007-1188}, journal={British Journal of Pharmacology}, pages={959--979}, author={Selenica, Maj-Linda and Jensen, Henning S. and Larsen, Anna Kirstine and Pedersen, M. L. and Helboe, Lone and Leist, Marcel and Lotharius, Julie} }

Helboe, Lone Publ. in: British Journal of Pharmacology ; 152 (2007), 6. - S. 959-979 Lotharius, Julie Larsen, Anna Kirstine Helboe, Lone Lotharius, Julie 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.<br />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).<br />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.<br />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. Selenica, Maj-Linda Jensen, Henning S. Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation 2011-03-23T09:07:29Z Pedersen, M. L. Pedersen, M. L. deposit-license Leist, Marcel Larsen, Anna Kirstine 2011-03-23T09:07:29Z Leist, Marcel 2007-11 Jensen, Henning S. Selenica, Maj-Linda eng

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

Leist_Selenica_Efficacy.pdf 106

Das Dokument erscheint in:

KOPS Suche


Stöbern

Mein Benutzerkonto