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

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• Classical laboratory mouse strains (e.g., C57BL/6J) exhibit limited genetic diversity, potentially hindering Alzheimer's disease (AD) research translation.
• Existing AD mouse models, often based on these limited strains, may not fully capture the complexity of human AD pathology.

Purpose of the Study:

• To investigate whether incorporating natural genetic variation from wild-derived mouse strains can improve the translatability of AD mouse models.
• To characterize novel AD mouse models developed using wild-derived strains for their relevance to human AD.

Main Methods:

• Two common AD-associated transgenes (APPswe and PS1de9) were backcrossed onto three wild-derived mouse strains (CAST/EiJ, WSB/EiJ, PWK/PhJ).
• These novel AD mouse models were evaluated using a comprehensive suite of assays, including metabolic, functional, neuropathological, and transcriptional analyses.
• Brain transcriptional data were analyzed to identify the primary drivers of variation.

Main Results:

• Significant strain-, sex-, and genotype-specific differences were observed in cognitive function, neurodegeneration, amyloid plaque load, cerebrovascular health, and cerebral amyloid angiopathy.
• Mouse strain emerged as the most significant factor influencing brain transcriptional variation.
• Substantial variation in myeloid cell populations was noted in wild-type mice across different strains, alongside distinct plaque-associated myeloid responses in the APP/PS1 AD models.

Conclusions:

• Wild-derived mouse strains offer greater genetic diversity, making them valuable for developing more translatable AD models.
• The observed strain-specific variations highlight the importance of considering genetic background in AD research.
• These findings support the use of genetically diverse mouse models to better recapitulate the complexity of human Alzheimer's disease.