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J. Biol. Chem., Vol. 279, Issue 39, 40987-40993, September 24, 2004
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**¶¶
From the
Program in Neurosciences, Department of Neurology, ||Department of Medicine, **Department of Molecular Biology and Pharmacology, Center for the Study of Nervous System Injury, Alzheimer's Disease Research Center, Washington University, St. Louis, Missouri 63110 and the ¶Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
ABCA1 is an ATP-binding cassette protein that transports cellular cholesterol and phospholipids onto high density lipoproteins (HDL) in plasma. Lack of ABCA1 in humans and mice causes abnormal lipidation and increased catabolism of HDL, resulting in very low plasma apoA-I, apoA-II, and HDL. Herein, we have used Abca1-/- mice to ask whether ABCA1 is involved in lipidation of HDL in the central nervous system (CNS). ApoE is the most abundant CNS apolipoprotein and is present in HDL-like lipoproteins in CSF. We found that Abca1-/- mice have greatly decreased apoE levels in both the cortex (80% reduction) and the CSF (98% reduction). CSF from Abca1-/- mice had significantly reduced cholesterol as well as small apoE-containing lipoproteins, suggesting abnormal lipidation of apoE. Astrocytes, the primary producer of CNS apoE, were cultured from Abca1+/+, +/-, and -/- mice, and nascent lipoprotein particles were collected. Abca1-/- astrocytes secreted lipoprotein particles that had markedly decreased cholesterol and apoE and had smaller apoE-containing particles than particles from Abca1+/+ astrocytes. These findings demonstrate that ABCA1 plays a critical role in CNS apoE metabolism. Since apoE isoforms and levels strongly influence Alzheimer's disease pathology and risk, these data suggest that ABCA1 may be a novel therapeutic target.
Received for publication, July 14, 2004
* This work was supported by National Institutes of Health Grants AG13956, P50-AG05681, and NS034467 (to D. M. H.). 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.
¶¶ To whom correspondence should be addressed: Washington University School of Medicine, Dept. of Neurology, 660 S. Euclid Ave., Box 8111, St. Louis, MO 63110. Tel.: 314-362-9872; Fax: 314-362-1771; E-mail: holtzman{at}neuro.wustl.edu.
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