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Rodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice

Jankowsky, Joanna L. and Younkin, Linda H. and Gonzales, Victoria and Fadale, Daniel J. and Slunt, Hilda H. and Lester, Henry A. and Younkin, Steven G. and Borchelt, David R. (2007) Rodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice. Journal of Biological Chemistry, 282 (31). pp. 22707-22720. ISSN 0021-9258. PMCID PMC4435736. https://resolver.caltech.edu/CaltechAUTHORS:JANjbc07

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Abstract

The amino acid sequence of amyloid precursor protein (APP) is highly conserved, and age-related Abeta 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 Abeta that might contribute to their differing properties in vivo. To examine the amyloidogenic potential of mouse Abeta, 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 Abeta could accelerate the deposition of human Abeta 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 Abeta but formed amyloid deposits no faster and to no greater extent than APPswe/PS1dE9 siblings. Instead, the additional mouse Abeta increased the detergent solubility of accumulated amyloid and exacerbated amyloid deposition in the vasculature. These findings suggest that, although mouse Abeta does not influence the rate of amyloid formation, the incorporation of Abeta peptides with differing sequences alters the solubility and localization of the resulting aggregates.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435736/PubMed CentralArticle
https://doi.org/10.1074/jbc.M611050200DOIUNSPECIFIED
https://doi.org/10.1074/jbc.M611050200DOIUNSPECIFIED
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2007 the American Society for Biochemistry and Molecular Biology. Received for publication, November 30, 2006, and in revised form, April 20, 2007. Originally published In Press as doi:10.1074/jbc.M611050200 on June 15, 2007. Originally published In Press as doi:10.1074/jbc.M611050200 on June 7, 2007. We thank Gay Rudow for advice on stereology, Eduardo Marcora for help with the Odyssey imager, and Neil Segil for sharing his ultracentrifuge for this work. We are grateful to Takeda Chemical Industries Co., Ltd. for providing antibodies BAN50, BNT77, BA27, and BC05, and to Konrad Beyreuther and Andreas Weidemann for sharing the 22C11 antibody. We thank David Teplow for providing mouse and human Abeta peptide standards, and David Holtzman for sharing peptide electrophoresis protocols. 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.
Funders:
Funding AgencyGrant Number
NIH1 P50 AG-14-248
NIH1 P01 AG-98-003
NIHAG-06-656
Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research ProgramUNSPECIFIED
Issue or Number:31
PubMed Central ID:PMC4435736
Record Number:CaltechAUTHORS:JANjbc07
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:JANjbc07
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8527
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:17 Aug 2007
Last Modified:02 Oct 2019 23:51

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