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 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, APP(swe) and PS1(de9) (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. Author summary Despite the rise in incidence of Alzheimer's disease (AD), it has been over a decade since a new drug treatment has been introduced. Recently, a number of pharmaceutical giants have shut down their AD research units. One issue that these companies and researchers have struggled with is the lack of translatability of preclinical studies to the clinic. One aspect that has come under heavy scrutiny is whether the mouse can be an appropriate model for a complex human disease such as AD. Current mouse models of AD have incorporated well-known early onset AD mutations on a single genetic background, C57BL/6J, which does not develop all features of human AD- namely marked neurodegeneration. Here we sought to improve the utility and translatability of mouse models through the use of three genetically distinct, wild-derived inbred mouse strains, CAST/EiJ, WSB/EiJ and PWK/PhJ. These mice encompass millions of genetic differences that have never before been explored in the context of modeling AD. Wild-derived mice that carried the early onset AD mutations exhibited robust differences in immune response to amyloid, evidence of mixed pathology and early neurodegeneration, better recapitulating what happens in human AD than previous models.