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J. Biol. Chem., Vol. 280, Issue 52, 43236-43242, December 30, 2005

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Deletion of Abca1 Increases A Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease^*

Suzanne E. Wahrle, Hong Jiang, Maia Parsadanian, Richard E. Hartman, Kelly R. Bales¶, Steven M. Paul¶, and David M. Holtzman||**1

From the Program in Neurosciences, Departments of Neurology and ^||Molecular Biology and Pharmacology, and ^**Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110 and ^¶Neuroscience Discovery Research, Eli Lilly and Co., Lilly Research Laboratories, Indianapolis, Indiana 46285

Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid -peptide (A). Mice lacking the lipid transporter ABCA1 were found to have markedly decreased levels and lipidation of apoE in the central nervous system. We hypothesized that if Abca1^-/- mice were bred to the PDAPP mouse model of AD, PDAPP Abca1^-/ mice would have a phenotype similar to that of PDAPP Apoe^+/- and PDAPP Apoe^-/- mice, which develop less amyloid deposition than PDAPP Apoe^+/+ mice. In contrast to this prediction, 12-month-old PDAPP Abca ^-/- mice had significantly higher levels of hippocampal A, and cerebral amyloid angiopathy was significantly more common compared with PDAPP Abca1^+/+ mice. Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or A production. As expected, 3-month-old PDAPP Abca1^-/- mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1^-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble A. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.

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

^* This work was supported by National Institutes of Health Grants AG13956 and AG11355 and by Lilly. 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 To whom correspondence should be addressed: Dept. of Neurology, Washington University, 660 S. Euclid Ave, Box 8111, St. Louis, MO 63110. Tel.: 314-362-9872; Fax: 314-362-1771; E-mail: holtzman{at}neuro.wustl.edu.

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