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J. Biol. Chem., Vol. 280, Issue 52, 43243-43256, December 30, 2005

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The Absence of ABCA1 Decreases Soluble ApoE Levels but Does Not Diminish Amyloid Deposition in Two Murine Models of Alzheimer Disease^*

Veronica Hirsch-Reinshagen1, Luis F. Maia, Braydon L. Burgess2, Jean-Francois Blain¶3, Kathryn E. Naus, Sean A. McIsaac, Pamela F. Parkinson, Jennifer Y. Chan, Gavin H. Tansley, Michael R. Hayden||4, Judes Poirier¶5, William Van Nostrand**6, and Cheryl L. Wellington, Supported by a Canadian Institutes of Health Research new investigator salary award and by Canadian Institutes of Health Research Operating Grant MOP 67068 and the Alzheimer Society of Canada/Canadian Institutes of Health Research/AstraZeneca7

From the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada, the Department of Neurology, Hospital Geral de Santo Antonio 4099-001, Porto, Portugal, ^¶McGill Centre for Studies in Aging, Montreal, Quebec H4H 1R3, Canada, ^||Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada, and the ^**Department of Medicine, Stony Brook University, Stony Brook, New York 11794

ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate -amyloid (A) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable A levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo.

Received for publication, August 9, 2005 , and in revised form, September 19, 2005.

^* 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 fellowship from the Canadian Institutes of Health Research.

² Supported by the British Columbia Child and Family Research Institute.

³ Supported by a fellowship from the Canadian Institutes of Health Research.

⁴ Supported by grants from the Canadian Institutes of Health Research and the British Columbia and Yukon Heart and Stroke Foundation. Holder of a Canadian Research Chair in Human Genetics.

⁵ Supported by a Canadian Institutes of Health Research senior investigator career award and operating grants from Canadian Institutes of Health Research and the Alzheimer Society of Canada.

⁶ Supported by the National Institutes of Health Grant NS36645.

⁷ To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of British Columbia, 980 West 28th Ave., Vancouver, British Columbia V5Z 4H4, Canada. Tel.: 604-875-2000 (ext. 6825); Fax: 604-875-3120; E-mail: cheryl{at}cmmt.ubc.ca.

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