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J. Biol. Chem., Vol. 280, Issue 27, 25754-25759, July 8, 2005

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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^*

From the Departments of ^aNeurology,^h Molecular Biology and Pharmacology,^c Pediatrics, and ^gCell Biology and Physiology and ⁱHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, ^bNeuroscience Discovery Research, Eli Lilly and Co., Lilly Research Laboratories, Indianapolis, Indiana 46285, Departments of^d Pharmacology and Toxicology and^e Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46285, and ^fBryan Alzheimer's Disease Research Center and Division of Neurology, Department of Medicine, Duke University, Medical Center, Durham, North Carolina 27710

Apolipoprotein E (apoE), a chaperone for the amyloid (A) peptide, regulates the deposition and structure of A 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 A levels either before or after the onset of A 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 A levels or deposition by 10 months of age in PDAPP mice, it remains a possibility that the increase in human apoE3 and apoE4 levels caused by LDLR deficiency will affect this process and could hold promise for therapeutic targets in AD.

Received for publication, February 24, 2005 , and in revised form, April 25, 2005.

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

^j To whom correspondence should be addressed: Dept. of Neurology, Campus Box 8111, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-9872; Fax: 314-362-2826; E-mail: holtzman{at}wustl.edu.

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