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J. Biol. Chem., Vol. 282, Issue 5, 2851-2861, February 2, 2007

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Role of ABCG1 and ABCA1 in Regulation of Neuronal Cholesterol Efflux to Apolipoprotein E Discs and Suppression of Amyloid- Peptide Generation^*

Woojin Scott Kim, Aldwin Suryo Rahmanto, Alvin Kamili, Kerry-Anne Rye, Gilles J. Guillemin^¶, Ingrid C. Gelissen^||**1, Wendy Jessup^||**, Andrew F. Hill, and Brett Garner^**2

From the Prince of Wales Medical Research Institute, Sydney, New South Wales 2031, The Heart Research Institute, Sydney, New South Wales 2050, the ^¶Centre for Immunology, St. Vincent's Hospital, Sydney, New South Wales 2010, the ^||Centre for Vascular Research and ^**School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052, and the Department of Biochemistry and Molecular Biology and Department of Pathology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia

Maintenance of an adequate supply of cholesterol is important for neuronal function, whereas excess cholesterol promotes amyloid precursor protein (APP) cleavage generating toxic amyloid- (A) peptides. To gain insights into the pathways that regulate neuronal cholesterol level, we investigated the potential for reconstituted apolipoprotein E (apoE) discs, resembling nascent lipoprotein complexes in the central nervous system, to stimulate neuronal [³H]cholesterol efflux. ApoE discs potently accelerated cholesterol efflux from primary human neurons and cell lines. The process was saturable (17.5 µg of apoE/ml) and was not influenced by APOE genotype. High performance liquid chromatography analysis of cholesterol and cholesterol metabolites effluxed from neurons indicated that <25% of the released cholesterol was modified to polar products (e.g. 24-hydroxycholesterol) that diffuse from neuronal membranes. Thus, most cholesterol (75%) appeared to be effluxed from neurons in a native state via a transporter pathway. ATP-binding cassette transporters ABCA1, ABCA2, and ABCG1 were detected in neurons and neuroblastoma cell lines and expression of these cDNAs revealed that ABCA1 and ABCG1 stimulated cholesterol efflux to apoE discs. In addition, ABCA1 and ABCG1 expression in Chinese hamster ovary cells that stably express human APP significantly reduced A generation, whereas ABCA2 did not modulate either cholesterol efflux or A generation. These data indicate that ABCA1 and ABCG1 play a significant role in the regulation of neuronal cholesterol efflux to apoE discs and in suppression of APP processing to generate A peptides.

Received for publication, August 16, 2006 , and in revised form, November 20, 2006.

^* This work was supported in part by Australian National Health and Medical Research Council Grants 350810 (to B. G.) and 222722 (to K.-A. R. and W. J.). 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.

¹ Supported by a Vice Chancellor Fellowship from the University of New South Wales.

² To whom correspondence should be addressed: Prince of Wales Medical Research Institute, Sydney, New South Wales 2031, Australia. Tel.: 61-2-93991024; Fax: 61-2-93991005; E-mail: brett.garner{at}unsw.edu.au.

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