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J. Biol. Chem., Vol. 282, Issue 31, 22707-22720, August 3, 2007

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Rodent A Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice^*

Joanna L. Jankowsky, Supported by the John Douglas French Alzheimer's Foundation and by NIA, National Institutes of Health Grant KO1 AG-26144-01¹, Linda H. Younkin, Victoria Gonzales^¶, Daniel J. Fadale, Hilda H. Slunt^||, Henry A. Lester, Steven G. Younkin, and David R. Borchelt^||2

From the Division of Biology, California Institute of Technology, Pasadena, California 91125, the Mayo Clinic Jacksonville, Jacksonville, Florida 32224, the ^¶Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the ^||Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610

The amino acid sequence of amyloid precursor protein (APP) is highly conserved, and age-related A aggregates have been described in a variety of vertebrate animals, with the notable exception of mice and rats. Three amino acid substitutions distinguish mouse and human A that might contribute to their differing properties in vivo. To examine the amyloidogenic potential of mouse A, we studied several lines of transgenic mice overexpressing wild-type mouse amyloid precursor protein (moAPP) either alone or in conjunction with mutant PS1 (PS1dE9). Neither overexpression of moAPP alone nor co-expression with PS1dE9 caused mice to develop Alzheimer-type amyloid pathology by 24 months of age. We further tested whether mouse A could accelerate the deposition of human A by crossing the moAPP transgenic mice to a bigenic line expressing human APPswe with PS1dE9. The triple transgenic animals (moAPP x APPswe/PS1dE9) produced 20% more A but formed amyloid deposits no faster and to no greater extent than APPswe/PS1dE9 siblings. Instead, the additional mouse A increased the detergent solubility of accumulated amyloid and exacerbated amyloid deposition in the vasculature. These findings suggest that, although mouse A does not influence the rate of amyloid formation, the incorporation of A peptides with differing sequences alters the solubility and localization of the resulting aggregates.

Received for publication, November 30, 2006 , and in revised form, April 20, 2007.

^* This work was supported in part by NIA, National Institutes of Health Grants 1 P50 AG-14-248 and 1 P01 AG-98-003 (to D. R. B.) and AG-06-656 (to S. G. Y.), the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program (to S. G. Y.). 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 may be addressed: California Institute of Technology, M.C. 156-29, Pasadena, CA 91125. Tel.: 626-395-6884; Fax: 626-564-8709; E-mail: jlj2{at}caltech.edu. ² To whom correspondence may be addressed: Dept. of Neuroscience, McKnight Brain Institute, University of Florida, 100 Newell Drive, Rm. L1-100H, P. O. Box 100244, Gainesville, FL 32610-0244. Tel.: 352-294-010; Fax: 352-392-8347; E-mail: borchelt{at}mbi.ufl.edu.

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