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12/12/2005 4:20:35 PM
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APOE function
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ApoE is the major lipoprotein within the CNS and it is synthesized by astrocytes. It is the primary cholesterol transporter in the brain, where it is proposed to function as a ligand directing the delivery of lipids for neuronal repair and remodelling after injury (reviewed by Mahley and Rall 2000 It may also be required for neuronal plasticity. There are 6 brain receptors for the ApoE ligand, including the low density lipoprotein related protein (LRP) (Holtzman et al 1995 and ApoER2 (Weeber et al 2002 Although the precise mechanism of how ApoE contributes to AD pathogenicity remains speculative, evidence suggests that it involves functions of ApoE unrelated to lipid transport that are influenced by the differential actions of ApoE isoforms (reviewed by Weisgraber and Mahley 1996

Consistent with its role as an AD susceptibility factor, the ε4 isoform has been shown to be the least biologically efficient form of ApoE, whereas ε2 is the most efficient. These differences have been observed with regards to neurite extension, binding and clearance of APP/Aβ (Strittmatter et al 1993 Yang et al 1997 Yang et al 1999 antioxidant activity (Miyata and Smith 1996 Lauderback et al 2002 mediation of cholesterol efflux (Kojro et al 2001 and positive inhibition of tau phosphorylation by GSK3β (Cedazo-Minguez et al 2003 Indeed, experiments in transgenic mice indicate that the ε4 allele is less able to bind Aβ and promote its clearance via LRP-mediated degradation, leading to increased deposition of fibrillar Aβ (Bales et al 1997 Holtzman et al 2000 Dodart et al 2005 Aβ induces cellular oxidative stress, indicating that observed antioxidant activity may be related to clearance of Aβ. Furthermore, decreases in the cholesterol efflux may affect membrane fluidity, and high cholesterol levels are reported to increase Aβ generation (reviewed by Puglielli et al 2003 suggesting a possible autocatalytic spiral. In addition, overexpression of ε4 leads to tau hyperphosphorylation by an as yet unknown mechanism (Tesseur et al 2000 Moreover, ApoE is likely to have an effect on cognitive processes, since ApoER2 is a receptor for the reelin protein. Binding of reelin to ApoER2 modulates hippocampal synaptic plasticity and learning and this is inhibited by ApoE, especially the ε4 isoform (Weeber et al 2002

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APOE function