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.
Highlights
Alzheimer’s disease (AD) is the most common cause of adult dementia, with approximately 6 million Americans diagnosed with either clinical AD or mild cognitive impairment in 2017[1]
Despite the rise in incidence of Alzheimer’s disease (AD), it has been over a decade since a new drug treatment has been introduced
A number of pharmaceutical giants have shut down their AD research units
Summary
Alzheimer’s disease (AD) is the most common cause of adult dementia, with approximately 6 million Americans diagnosed with either clinical AD or mild cognitive impairment in 2017[1]. AD is pathologically characterized by the accumulation of beta amyloid (β-amyloid) plaques, neurofibrillary tangles, and widespread neuronal loss. Another prominent feature is the neuroinflammatory response by a variety of cells including astrocytes and microglia. While FAD mouse models have been vital to understand early drivers of amyloidosis, to date, they do not effectively model all hallmarks of AD, frank neurodegeneration. This has led some to question the utility of mouse models as preclinical models for AD and other diseases of complex etiologies
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