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The Journal of Neuroscience, May 27, 2009, 29(21):6771-6779; doi:10.1523/JNEUROSCI.0887-09.2009

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Neurobiology of Disease
Human APOE Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

Kelly R. Bales,¹ Feng Liu,¹ Su Wu,¹ Suizhen Lin,¹ Deanna Koger,¹ Cynthia DeLong,¹ Jeffrey C. Hansen,² Patrick M. Sullivan,³ and Steven M. Paul¹

¹Neuroscience Discovery Research and ²Discovery Informatics, Eli Lilly and Company, Indianapolis, Indiana 46285, and ³Department of Medicine, Centers for Aging and Geriatric Research Education and Clinical Center, Durham Veteran Affairs Medical Center, Duke University, Durham, North Carolina 27710

Correspondence should be addressed to either of the following: Kelly R. Bales (at her present address), Neuroscience Research Unit, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, Email: Kelly.Bales{at}Pfizer.com; or Steven M. Paul, Neuroscience Discovery Research, Eli Lilly and Company, 355 East Merrill Street, Indianapolis, IN 46285, Email: Paul_Steven_M{at}lilly.com

To investigate the role of human apolipoprotein E (apoE) on Aβ deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE protein and Aβ peptides in plasma, CSF, and brain homogenates in these mice at different ages. We also quantified the amount of brain Aβ and amyloid burden in 18-month-old mice. In young PDAPP/TRE4 mice that were analyzed at an age before brain Aβ deposition, we observed a significant decrease in the levels of apoE in CSF and brain when compared with age-matched mice expressing either human E2 or E3. The brain levels of Aβ42 in PDAPP/TRE4 mice were substantially elevated even at this very early time point. In older PDAPP/TRE4 mice, the levels of insoluble apoE protein increased in parallel to the dramatic rise in brain Aβ burden, and the majority of apoE was associated with Aβ. In TRE4 only mice, we also observed a significant decrease in the level of apoE in brain homogenates. Since the relative level of apoE mRNA was equivalent in PDAPP/TRE and TRE only mice, it appears that post-translational mechanisms influence the levels of apoE protein in brain (E4 < E3 << E2), resulting in early and dramatic apoE isoform-dependent effects on brain Aβ levels (E4 >> E3 > E2) that increase with age. Therapeutic strategies aimed at increasing the soluble levels of apoE protein, regardless of isoform, may effectively prevent and (or) treat Alzheimer's disease.

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Received Feb. 20, 2009; revised March 18, 2009; accepted April 8, 2009.

Correspondence should be addressed to either of the following: Kelly R. Bales (at her present address), Neuroscience Research Unit, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, Email: Kelly.Bales{at}Pfizer.com; or Steven M. Paul, Neuroscience Discovery Research, Eli Lilly and Company, 355 East Merrill Street, Indianapolis, IN 46285, Email: Paul_Steven_M{at}lilly.com

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