Chunk #34 — Converging Pathways Implicated in Neurogenesis and AD Pathology — Wnt, reelin and the low-density lipoprotein receptor family in neurogenesis and AD
protect against Aβ toxicity (Cheng et al., 2009). Finally, reelin expression has recently been shown to be downregulated in APP transgenic mice and in AD (Chin et al., 2007). Other LDLR family members including LRP1, LRP1B, and LR11/sorLA have also been shown to modulate APP processing [For review see (Marzolo and Bu, 2009)]. LRP5 and LRP6 are LDLR family members that function as co-receptors required for Wnt signaling. As discussed above, wnt functions to inhibit GSK3 and so plays a role in modulation of tau phosphorylation in AD. However the effects of wnt on AD pathology are not limited to potential modulation of tau phosphorylation. Lithium, a potent inhibitor of GSK3 activity, was shown to substantially reduce levels of Aβ, in vitro and in vivo (Phiel et al., 2003). RNA interference experiments showed that the α and β isoforms of GSK3 produced opposite effects on Aβ levels indicating a more complex relationship to APP processing (Phiel et al., 2003). Furthermore, it has also been shown that lithium could ameliorate neurodegeneration induced by Aβ fibrils and improve memory performance in rats (De Ferrari et al., 2003). However, the potential effects of lithium on Aβ pathology remain controversial as a more recent
