Neuronal death and GSK-3β: a tau fetish?

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The microtubule-associated protein tau is hyperphosphorylated in neurons that degenerate in Alzheimer's disease and related disorders and it has therefore been suggested, but never established, that such hyperphosphorylation of tau is a crucial event in disease pathogenesis. Among the many different kinases that can phosphorylate tau, glycogen synthase kinase-3β (GSK-3β) has recently received considerable attention because of its emerging roles in the process of apoptosis. Two recent studies highlight the nebulous nature of the link between phosphorylation of tau by GSK-3β on the one hand, and the involvement of GSK-3β in neuronal death, on the other. Lucas and colleagues 1 Lucas J.J et al. Decreased nuclear β-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3β conditional transgenic mice. EMBO J. 2001; 20: 27-39 Crossref PubMed Scopus (796) Google Scholar produced transgenic mice in which expression of GSK-3β is under the control of a tetracycline-sensitive transactivator that allows the expression of the transgene to be turned on when required. Because overexpression of GSK-3β might have adverse effects on the developing embryo, Lucas et al. induced expression of GSK-3β only after birth to determine the effects of excessive levels of GSK-3β activity on the brain. They observed tau hyperphosphorylation and evidence of neuronal degeneration and glial reactivity that were most prominent in the dentate gyrus of the hippocampus. They concluded that ‘in vivo overexpression of GSK-3β results in neurodegeneration’ and that ‘deregulation of GSK-3β might be a critical event in the pathogenesis of Alzheimer's disease’. In another study, Spittaels and coworkers 2 Spittaels K et al. Glycogen synthase kinase-3β phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J. Biol. Chem. 2000; 275: 41340-41349 Crossref PubMed Scopus (278) Google Scholar generated transgenic mice that overexpressed a phosphorylation-insensitive (constitutively active) GSK-3β (GSK-3βca mice); these mice developed normally and showed neither overt phenotypes nor evidence of neuronal degeneration in their CNS. Mice that overexpress a four-repeat form of human tau that mimics the genetic defect in some cases of inherited, chromosome 17-linked, frontotemporal dementia and parkinsonism (tau 40 mice) were then crossed with the GSK-3βca transgenic mice. Tau 40 mice develop quite severe degeneration of axons in both the brain and spinal cord. Surprisingly, although tau in the double transgenic mice exhibited increased phosphorylation and decreased microtubule binding, the axonal pathology was actually decreased. Thus, overexpression of GSK-3β can either promote or prevent neuronal degeneration regardless of increased tau hyperphosphorylation.