Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation.
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...
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2019-05-01
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Series: | PLoS Genetics |
Online Access: | https://doi.org/10.1371/journal.pgen.1008155 |
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doaj-0d81041fb4e046249530dd01712fb4ef2021-04-21T14:22:04ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042019-05-01155e100815510.1371/journal.pgen.1008155Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation.Kristen D OnosAsli UyarKelly J KeezerHarriet M JacksonChristoph PreussCasey J AcklinRita O'RourkeRebecca BuchananTravis L CossetteStacey J Sukoff RizzoIleana SotoGregory W CarterGareth R HowellClassical 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.https://doi.org/10.1371/journal.pgen.1008155 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kristen D Onos Asli Uyar Kelly J Keezer Harriet M Jackson Christoph Preuss Casey J Acklin Rita O'Rourke Rebecca Buchanan Travis L Cossette Stacey J Sukoff Rizzo Ileana Soto Gregory W Carter Gareth R Howell |
spellingShingle |
Kristen D Onos Asli Uyar Kelly J Keezer Harriet M Jackson Christoph Preuss Casey J Acklin Rita O'Rourke Rebecca Buchanan Travis L Cossette Stacey J Sukoff Rizzo Ileana Soto Gregory W Carter Gareth R Howell Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. PLoS Genetics |
author_facet |
Kristen D Onos Asli Uyar Kelly J Keezer Harriet M Jackson Christoph Preuss Casey J Acklin Rita O'Rourke Rebecca Buchanan Travis L Cossette Stacey J Sukoff Rizzo Ileana Soto Gregory W Carter Gareth R Howell |
author_sort |
Kristen D Onos |
title |
Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. |
title_short |
Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. |
title_full |
Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. |
title_fullStr |
Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. |
title_full_unstemmed |
Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. |
title_sort |
enhancing face validity of mouse models of alzheimer's disease with natural genetic variation. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2019-05-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pgen.1008155 |
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