Enhancing face validity of mouse models of Alzheimer’s disease with natural genetic variation

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

    Research output: Contribution to journalArticlepeer-review

    19 Scopus citations

    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.

    Original languageEnglish (US)
    Article numbere1008155
    JournalPLoS Genetics
    Volume15
    Issue number5
    DOIs
    StatePublished - May 2019

    All Science Journal Classification (ASJC) codes

    • Ecology, Evolution, Behavior and Systematics
    • Molecular Biology
    • Genetics
    • Genetics(clinical)
    • Cancer Research

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