Chunk #32 — Converging Pathways Implicated in Neurogenesis and AD Pathology — Wnt, reelin and the low-density lipoprotein receptor family in neurogenesis and AD
Polymorphisms in the apolipoprotein E (apoE) gene show the most significant effects on relative genetic risk of sporadic AD. The ε4 isoform (Cyc112-Arg) of apoE is associated with increased risk of developing AD, while ε2 (Arg158-Cys) is associated with protection from the disease compared to the normal ε3 allele (Bu, 2009). This has been reproduced in gene modified mouse models of AD (Bales et al., 1999; Holtzman et al., 2000; Fagan et al., 2002). Furthermore, intrahippocampal lentiviral gene transfer of ε4 and ε2 can respectively promote and prevent AD-like pathology in APP transgenic mice (Dodart et al., 2005). ApoE binds to every member of a class of receptors known as the low-density lipoprotein receptors (LDLR) [reviewed in (Herz, 2001)]. There are upwards of 10 members to this family of receptors. Classically they have been shown to function in cholesterol and lipid transport. However, this large receptor family has also been shown to function as signal transducers (Hoe et al., 2005a). Blocking the LDLR family results in embryonic lethality as a result of the inability to form mesoderm (Herz and Marschang, 2003; Hsieh et al., 2003).
