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Journal of Lipid Research, Vol. 48, 914-923, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid-ß peptide levels in vivo

Veronica Hirsch-Reinshagen^*, Jennifer Y. Chan^*, Anna Wilkinson^*, Tracie Tanaka^*, Jianjia Fan^*, George Ou^*, Luis F. Maia, Roshni R. Singaraja, Michael R. Hayden and Cheryl L. Wellington^1,*

^* Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
Department of Neurology, Hospital Geral de Santo Antonio, Porto, Portugal
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada

Published, JLR Papers in Press, January 18, 2007.

¹ To whom correspondence should be addressed. e-mail: cheryl{at}cmmt.ubc.ca

ABCA1-deficient mice have low levels of poorly lipidated apolipoprotein E (apoE) and exhibit increased amyloid load. To test whether excess ABCA1 protects from amyloid deposition, we crossed APP/PS1 mice to ABCA1 bacterial artificial chromosome (BAC) transgenic mice. Compared with wild-type animals, the ABCA1 BAC led to a 50% increase in cortical ABCA1 protein and a 15% increase in apoE abundance, demonstrating that this BAC supports modest ABCA1 overexpression in brain. However, this was observed only in animals that do not deposit amyloid. Comparison of ABCA1/APP/PS1 mice with APP/PS1 controls revealed no differences in levels of brain ABCA1 protein, amyloid, Aß, or apoE, despite clear retention of ABCA1 overexpression in the livers of these animals. To further investigate ABCA1 expression in the amyloid-containing brain, we then compared ABCA1 mRNA and protein levels in young and aged cortex and cerebellum of APP/PS1 and ABCA1/APP/PS1 animals. Compared with APP/PS1 controls, aged ABCA1/APP/PS1 mice exhibited increased ABCA1 mRNA, but not protein, selectively in cortex. Additionally, ABCA1 mRNA levels were not increased before amyloid deposition but were induced only in the presence of extensive Aß and amyloid levels. These data suggest that an induction of ABCA1 expression may be associated with late-stage Alzheimer's neuropathology.

Supplementary key words ATP binding cassette transporter A1 • apolipoprotein E • Alzheimer's disease • animal model

Abbreviations: Aß, amyloid-ß peptide; AD, Alzheimer's disease; apoE, apolipoprotein E; BAC, bacterial artificial chromosome; CNS, central nervous system; CSF, cerebrospinal fluid; LXR, liver X receptor; RXR, retinoic X receptor; Tg, transgenic; 24S-OH-Chol, 24S-hydroxycholesterol; 27-OH-Chol, 27-hydroxycholesterol

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