The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice

John D. Fryer, Ronald B. DeMattos, Lynn M. McCormick, Mark A. O'Dell, Michael L. Spinner, Kelly R. Bales, Steven M. Paul, Patrick M. Sullivan, Maia Parsadanian, Guojun Bu, David M. Holtzman

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Abstract

Apolipoprotein E (apoE), a chaperone for the amyloid β (Aβ) peptide, regulates the deposition and structure of Aβ that deposits in the brain in Alzheimer disease (AD). The primary apoE receptor that regulates levels of apoE in the brain is unknown. We report that the low density lipoprotein receptor (LDLR) regulates the cellular uptake and central nervous system levels of astrocyte-derived apoE. Cells lacking LDLR were unable to appreciably endocytose astrocyte-secreted apoE-containing lipoprotein particles. Moreover, cells overexpressing LDLR showed a dramatic increase in apoE endocytosis and degradation. We also found that LDLR knock-out (Ldlr-/-) mice had a significant, ∼50% increase in the level of apoE in the cerebrospinal fluid and extracellular pools of the brain. However, when the PDAPP mouse model of AD was bred onto an Ldlr-/- background, we did not observe a significant change in brain Aβ levels either before or after the onset of Aβ deposition. Interestingly, human APOE3 or APOE4 (but not APOE2) knock-in mice bred on an Ldlr-/- background had a 210% and 380% increase, respectively, in the level of apoE in cerebrospinal fluid. These results demonstrate that central nervous system levels of both human and murine apoE are directly regulated by LDLR. Although the increase in murine apoE caused by LDLR deficiency was not sufficient to affect Aβ levels or deposition by 10 months of age in PDAPP mice, it remains a possibility that the increase in human apoES and apoE4 levels caused by LDLR deficiency will affect this process and could hold promise for therapeutic targets in AD.

Original languageEnglish (US)
Pages (from-to)25754-25759
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number27
DOIs
StatePublished - Jul 8 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Fryer, J. D., DeMattos, R. B., McCormick, L. M., O'Dell, M. A., Spinner, M. L., Bales, K. R., Paul, S. M., Sullivan, P. M., Parsadanian, M., Bu, G., & Holtzman, D. M. (2005). The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. Journal of Biological Chemistry, 280(27), 25754-25759. https://doi.org/10.1074/jbc.M502143200