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IN order to investigate the effect on tau of manipulating glycogen synthase kinase (GSK)-3β activity in the brain, we created transgenic mice harbouring wild-type GSK-3β genes or a mutant GSK-3β that is predicted to be more active. Transgene-derived mRNAs were detected in the brains of a number of the transgenic mouse lines and several of these transgenic lines displayed transgenic GSK-3β activity. Western blot analyses of the two lines with the highest levels of transgenic GSK-3β activity revealed that the phosphorylation status of tau was elevated at the AT8 epitope. These observations strongly suggest that GSK-3β is an in vivo tau kinase in the brain. Only low levels of expression of GSK-3β were obtained and it is possible that high levels of GSK-3β activity are lethal.