Full text

Turn on search term navigation

© 2019 Onos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer’s disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APPswe and PS1de9 (APP/PS1), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were characterized using metabolic, functional, neuropathological and transcriptional assays. Strain-, sex- and genotype-specific differences were observed in cognitive ability, neurodegeneration, plaque load, cerebrovascular health and cerebral amyloid angiopathy. Analyses of brain transcriptional data showed strain was the greatest driver of variation. We identified significant variation in myeloid cell numbers in wild type mice of different strains as well as significant differences in plaque-associated myeloid responses in APP/PS1 mice between the strains. Collectively, these data support the use of wild-derived strains to better model the complexity of human AD.

Details

Title
Enhancing face validity of mouse models of Alzheimer’s disease with natural genetic variation
Author
Onos, Kristen D; Uyar, Asli; Keezer, Kelly J; Jackson, Harriet M; Preuss, Christoph; Acklin, Casey J; O'Rourke, Rita; Buchanan, Rebecca; Cossette, Travis L; Sukoff Rizzo, Stacey J; Soto, Ileana; Carter, Gregory W; Howell, Gareth R
First page
e1008155
Section
Research Article
Publication year
2019
Publication date
May 2019
Publisher
Public Library of Science
ISSN
15537390
e-ISSN
15537404
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2251079471
Copyright
© 2019 Onos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.