Document Type

Article

Publication Date

2019

Keywords

JMG

JAX Source

PLoS Genet 2019 May 31; 15(5):e1008155

PMID

31150388

DOI

https://doi.org/10.1371/journal.pgen.1008155

Grant

HD007065,AG055104,AG054345, The Jackson Laboratory startup funds

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.

Comments

The authors would like to acknowledge and extend thanks to Sam Groh for her efforts in establishing the initial mouse colonies. They would also like to acknowledge and extend thanks to the members of the JAX Center for Biometrics Analysis (particularly the MNBF and IVP teams).

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