brains. As discussed above, glycogen synthase kinase 3 (GSK3) is a component of the Wnt signaling pathway, that plays a major role in adult neurogenesis (Lie et al., 2005), microtubule dynamics and fast axonal transport (Frame et al., 2001; Morfini et al., 2002). GSK3 is inactivated by phosphorylation at serine 9 (Ser9) in its N′-terminus. Among GSK3's numerous substrates are PS1, β-catenin, tau, and kinesin-I light chains (KLC) [(Tesco and Tanzi, 2000; Morfini et al., 2002; Takashima et al., 1998) For review see (Frame and Cohen, 2001)]. Previous studies suggest that FAD-linked PS1 mutations affect GSK3 kinase activity in transfected cell lines (Takashima et al., 1998; Weihl et al., 1999a; Weihl et al., 1999b). Significantly, phosphorylation of KLC by GSK3 promotes the release of kinesin-I from membrane-bound organelles, leading to a reduction in fast anterograde axonal transport (Morfini et al., 2002). GSK3 has been recently suggested to play a role in the induction of mammalian neurogenesis in embryonic stem cells and in regulation of neurogenesis in the adult SVZ (Maurer et al., 2007), raising the possibility that alterations in GSK3 kinase activity in the SVZ and SGL microenvironments underlie alterations in tau phosphorylation in these neurogenic niches of adult mice.
