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The Journal of Neuroscience, November 5, 2008, 28(45):11445-11453; doi:10.1523/JNEUROSCI.1972-08.2008

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

David R. Riddell, Hua Zhou, Kevin Atchison, Helen K. Warwick, Peter J. Atkinson, Julius Jefferson, Lin Xu, Suzan Aschmies, Yolanda Kirksey, Yun Hu, Erik Wagner, Adrienne Parratt, Jane Xu, Zhuting Li, Margaret M. Zaleska, J. Steve Jacobsen, Menelas N. Pangalos, and Peter H. Reinhart

Discovery Neuroscience, Wyeth Research, CN8000, Princeton, New Jersey 08543

Correspondence should be addressed to Dr. David R. Riddell at the above address. Email: riddeld{at}wyeth.com

Inheritance of the apoE4 allele (4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of 4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of 2/2, 3/3, and 4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; 2/2 >3/3 >4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the 3/4 mouse brains. ApoE4 represented 30–40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between 3/3 and 3/4 mice, implying that the reduced levels of total apoE in 3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from 3/4 human astrocytoma or 3/3, 4/4 and 3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from 4/4 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 4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or Aβ clearance.

Key words: apolipoprotein E; astrocyte; degradation; Alzheimer's disease; immunoassay; liver X receptor

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Received Aug. 1, 2007; revised Aug. 4, 2008; accepted Aug. 15, 2008.

Correspondence should be addressed to Dr. David R. Riddell at the above address. Email: riddeld{at}wyeth.com

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