Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Discovery Neuroscience, Wyeth Research, CN8000, Princeton, New Jersey 08543, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2008; 28(45):11445-53. DOI: 10.1523/JNEUROSCI.1972-08.2008
Source: PubMed


Inheritance of the apoE4 allele (epsilon4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of epsilon4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of epsilon2/2, epsilon3/3, and epsilon4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; epsilon2/2 >epsilon3/3 >epsilon4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the epsilon3/4 mouse brains. ApoE4 represented 30-40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between epsilon3/3 and epsilon3/4 mice, implying that the reduced levels of total apoE in epsilon3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from epsilon3/4 human astrocytoma or epsilon3/3, epsilon4/4 and epsilon3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from epsilon4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by epsilon4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or Abeta clearance.

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    • "As a major lipid transporter and redistribution regulator in the brain (Mahley et al, 2006), impaired apoE function exhibited by APOE-e4 carriers may give rise to abnormal cholesterol homeostasis (Jiang et al, 2008; Riddell et al, 2008). "
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    • "Indeed, animal and in vitro experiments have suggested that enhanced degradation or defective lipidation of the ApoE4 protein compared with ApoE3 stand as possible explanations for a reduction in total ApoE in tissue [81] [88]. Brain ApoE concentrations are also decreased in AD brain [45] [74] [89] and plasma [90], further arguing for a loss of ApoE activity in AD. "
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