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Originally published In Press as doi:10.1074/jbc.M300044200 on January 22, 2003

J. Biol. Chem., Vol. 278, Issue 15, 13244-13256, April 11, 2003
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22R-Hydroxycholesterol and 9-cis-Retinoic Acid Induce ATP-binding Cassette Transporter A1 Expression and Cholesterol Efflux in Brain Cells and Decrease Amyloid beta  Secretion*

Radosveta P. KoldamovaDagger §, Iliya M. LefterovDagger , Milos D. Ikonomovic, John SkokoDagger , Preslav I. LefterovDagger , Barbara A. Isanski, Steven T. DeKosky, and John S. LazoDagger §

From the Departments of Dagger  Pharmacology and  Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of peripheral cholesterol efflux and plasma high density lipoprotein metabolism. In adult rat brain we found high expression of ABCA1 in neurons in the hypothalamus, thalamus, amygdala, cholinergic basal forebrain, and hippocampus. Large neurons of the cholinergic nucleus basalis together with CA1 and CA3 pyramidal neurons were among the most abundantly immunolabeled neurons. Glia cells were largely negative. Because cholesterol homeostasis may have an essential role in central nervous system function and neurodegeneration, we examined ABCA1 expression and function in different brain cell types using cultures of primary neurons, astrocytes, and microglia isolated from embryonic rat brain. The basal ABCA1 mRNA and protein levels detected in these cell types were increased markedly after exposure to oxysterols and 9-cis-retinoic acid, which are ligands for the nuclear hormone liver X receptors and retinoic X receptors, respectively. Functionally, the increased ABCA1 expression caused by these ligands was followed by elevated apoA-I- and apoE-specific cholesterol efflux in neurons and glia. In non-neuronal and neuronal cells overexpressing a human Swedish variant of amyloid precursor protein, 22R-hydroxycholesterol and 9-cis-retinoic acid induced ABCA1 expression and increased apoA-I-mediated cholesterol efflux consequently decreasing cellular cholesterol content. More importantly, we demonstrated that these ligands alone or in combination with apoA-I caused a substantial reduction in the stability of amyloid precursor protein C-terminal fragments and decreased amyloid beta  production. These effects of 22R-hydroxycholesterol may provide a novel strategy to decrease amyloid beta  secretion and consequently reduce the amyloid burden in the brain.

* This work was supported by a pilot grant from the Alzheimer's Disease Research Center Pittsburgh (to R. P. K.), a pilot grant from the Pittsburgh Institute for Neurodegenerative Disorders (to I. M. L.), National Institutes of Health Grant AG 18558 (to J. S. L.), and by the Fiske Drug Discovery Fund.The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Dept. of Pharmacology, E-1358 Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Tel.: 412-648-2052; Fax: 412-648-1945; E-mail: radak@pitt.edu or Lazo{at}pitt.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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