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Experimental Genetics Group

Bolleke Abstract   Pijltje
Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice.

J Biol Chem. 2000 Dec 29;275(52):41340-9.

Spittaels K1,5, Van den Haute C1,5, Van Dorpe J1,5, Geerts H2, Mercken M2, Bruynseels K1, Lasrado R1, Vandezande K1, Laenen I1, Boon T1, Van Lint J3, Vandenheede J3, Moechars D2, Loos R4, Van Leuven F1.

1Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium.
2Janssen Research Foundation, Beerse, Belgium.
3Department of Biochemistry, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
4Department of Genetic Epidemiology, Katholieke Universiteit Leuven, Leuven, Belgium.
5These authors contributed equally to this work.

Protein tau filaments in brain of patients suffering from Alzheimer's disease, frontotemporal dementia, and other tauopathies consist of protein tau that is hyperphosphorylated. The responsible kinases operating in vivo in neurons still need to be identified. Here we demonstrate that glycogen synthase kinase-3beta (GSK-3beta) is an effective kinase for protein tau in cerebral neurons in vivo in adult GSK-3beta and GSK-3beta x human tau40 transgenic mice. Phosphorylated protein tau migrates slower during electrophoretic separation and is revealed by phosphorylation-dependent anti-tau antibodies in Western blot analysis. In addition, its capacity to bind to re-assembled paclitaxel (Taxol((R)))-stabilized microtubules is reduced, compared with protein tau isolated from mice not overexpressing GSK-3beta. Co-expression of GSK-3beta reduces the number of axonal dilations and alleviates the motoric impairment that was typical for single htau40 transgenic animals (Spittaels, K., Van den Haute, C., Van Dorpe, J., Bruynseels, K., Vandezande, K., Laenen, I., Geerts, H., Mercken, M., Sciot, R., Van Lommel, A., Loos, R., and Van Leuven, F. (1999) Am. J. Pathol. 155, 2153-2165). Although more hyperphosphorylated protein tau is available, neither an increase in insoluble protein tau aggregates nor the presence of paired helical filaments or tangles was observed. These findings could have therapeutic implications in the field of neurodegeneration, as discussed.

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