Glycogen synthase kinase-3 beta phosphorylates protein tau and rescues theaxonopathy in the central nervous system of human four-repeat tau transgenic mice

Protein tau filaments in brain of patients suffering from Alzheimer's disea se, frontotemporal dementia, and other tauopathies consist of protein tau t hat is hyperphosphorylated.,The responsible kinases operating in vivo in ne urons still need to be identified. Here we demonstrate that glycogen syntha se kinase-3 beta (GSK-3 beta) is an effective kinase for protein tau in cer ebral neurons in vivo in adult GSK-3 beta and GSK-3 beta x human tau40 tran sgenic mice; Phosphorylated protein tau migrates slower during electrophore tic separation and is revealed by phosphorylation-dependent anti-tau antibo dies in Western blot analysis. In addition, its capacity to bind to re-asse mbled paclitaxel (Taxol(R))-stabilized microtubules is reduced, compared wi th protein tau isolated from mice not overexpressing GSK-3 beta. Co-express ion of GSK-3 beta 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 mor e hyperphosphorylated protein tau is available, neither an increase in inso luble protein tau aggregates nor the presence of paired helical filaments o r tangles was observed. These findings could have therapeutic implications in the field of neurodegeneration, as discussed.