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J. Biol. Chem., Vol. 280, Issue 52, 43224-43235, December 30, 2005

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Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice^*

Radosveta Koldamova12, Matthias Staufenbiel, and Iliya Lefterov¶1

From the Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, Novartis Institutes of BioMedical Research, CH-4002 Basel, Switzerland, and ^¶Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

ABCA1 (ATP-binding cassette transporter A1) is a major regulator of cholesterol efflux and high density lipoprotein (HDL) metabolism. Mutations in human ABCA1 cause severe HDL deficiencies characterized by the virtual absence of apoA-I and HDL and prevalent atherosclerosis. Recently, it has been reported that the lack of ABCA1 causes a significant reduction of apoE protein level in the brain of ABCA1 knock-out (ABCA1^-/-) mice. ApoE isoforms strongly affect Alzheimer disease (AD) pathology and risk. To determine further the effect of ABCA1 on amyloid deposition, we used APP23 transgenic mice in which the human familial Swedish AD mutant is expressed only in neurons. We demonstrated that the targeted disruption of ABCA1 increases amyloid deposition in APP23 mice, and the effect is manifested by an increased level of A immunoreactivity, as well as thioflavine S-positive plaques in brain parenchyma. We found that the lack of ABCA1 also considerably increased the level of cerebral amyloid angiopathy and exacerbated cerebral amyloid angiopathy-related microhemorrhage in APP23/ABCA1^-/- mice. Remarkably, the elevation in parenchymal and vascular amyloid in APP23/ABCA1^-/- mice was accompanied by a dramatic decrease in the level of soluble brain apoE, although insoluble apoE was not changed. The elevation of insoluble A fraction in old APP23/ABCA1^-/- mice, accompanied by a lack of changes in APP processing and soluble -amyloid in young APP23/ABCA1^-/- animals, supports the conclusion that the ABCA1 deficiency increases amyloid deposition. These results suggest that ABCA1 plays a role in the pathogenesis of parenchymal and cerebrovascular amyloid pathology and thus may be considered a therapeutic target in AD.

Received for publication, April 25, 2005 , and in revised form, September 19, 2005.

^* This work was supported in part by Neurosciences Education and Research Foundation (to R. K.) and NIA Grants AG023662 (to R. K.) and AG023304 (to I. L.) from the National Institutes of Health. 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.

² Present address: Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15260.

¹ To whom correspondence should be addressed. Dept. of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260. Tel.: 412-383-6906; E-mail: radak{at}pitt.edu or iliyal{at}pitt.edu.

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