Lipids and Lipoproteins
The Low Density Lipoprotein Receptor Regulates the Level of CentralNervous System Human and Murine Apolipoprotein E but Does Not Modify AmyloidPlaque Pathology in PDAPPMice*

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Apolipoprotein E (apoE), a chaperone for the amyloid β (Aβ)peptide, regulates the deposition and structure of Aβ that deposits inthe brain in Alzheimer disease (AD). The primary apoE receptor that regulateslevels of apoE in the brain is unknown. We report that the low densitylipoprotein receptor (LDLR) regulates the cellular uptake and central nervoussystem levels of astrocyte-derived apoE. Cells lacking LDLR were unable toappreciably endocytose astrocyte-secreted apoE-containing lipoproteinparticles. Moreover, cells overexpressing LDLR showed a dramatic increase inapoE endocytosis and degradation. We also found that LDLR knock-out(Ldlr-/-) mice had a significant, ∼50% increase in thelevel of apoE in the cerebrospinal fluid and extracellular pools of the brain.However, when the PDAPP mouse model of AD was bred onto anLdlr-/- background, we did not observe a significantchange in brain Aβ levels either before or after the onset of Aβdeposition. Interestingly, human APOE3 or APOE4 (but notAPOE2) knock-in mice bred on an Ldlr-/-background had a 210% and 380% increase, respectively, in the level of apoE incerebrospinal fluid. These results demonstrate that central nervous systemlevels of both human and murine apoE are directly regulated by LDLR. Althoughthe increase in murine apoE caused by LDLR deficiency was not sufficient toaffect Aβ levels or deposition by 10 months of age in PDAPP mice, itremains a possibility that the increase in human apoE3 and apoE4 levels causedby LDLR deficiency will affect this process and could hold promise fortherapeutic targets in AD.

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This work was supported by National Institutes of Health Grants AG13956,P50 AG05681, and AG11355; MetLife Foundation; and Eli Lilly and Co. The costsof publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked“advertisement” in accordance with 18 U.S.C. Section 1734solely to indicate this fact.