APOE ε3/ε4 and APOE ε4/ε4 genotypes drive unique gene signatures in the cortex of young mice

Background Restrictions on mouse models have significantly impacted research towards understanding the most common genotype contributing to dementia in the human population – APOE ε3/ε4 . To address this, as part of MODEL-AD, we created new versions of humanized APOE ε4 and APOE ε3 mice on a C57BL/6J background that allow for unrestricted distribution and breeding. Methods To determine similarities and differences between APOE ε3/ε4 and APOE ε4/ε4 risk genotypes, we analyzed peripheral lipid concentrations as well as performed unbiased transcriptional profiling of the cortex at two and four months of age, comparing APOE ε3/ε4 and APOE ε4/ε4 to the reference APOE ε3/ε3 . To further compare APOE genotypes, cohorts of APOE ε3/ε3 , APOE ε3/ε4 , and APOE ε4/ε4 mice were exercised by voluntary running from 1 month to 4 months of age. Results Cholesterol composition was significantly influenced by APOE genotype as early as 2 months, while triglycerides were affected by APOE genotype at 4 months. Importantly, RNA-sequencing of the cortex followed by linear modeling or weighted gene co-expression network analysis (WGCNA) revealed that the APOE ε3/ε4 genotype showed unique transcriptomic signatures to that of APOE ε4/ε4 . Functional enrichment of the APOE ε3/ε4 , but not APOE ε3/ε4 genotype, revealed sulfur and heparin binding as significant terms at 2 months, and extracellular matrix and blood coagulation at 4 months. Further, cell specific contributions of significant genes identified endothelial cells as overrepresented in the APOE ε3/ε4 but not APOE ε4/ε4 genotype. WGCNA analysis confirmed findings from linear modeling but also predicted that running at a young age affects myelination and gliogenesis across APOE genotypes. Conclusions In summary, APOE ε3/ε4 genotype-specific effects were observed in cortical transcriptional profiles, suggesting therapies aimed at modifying APOE biology to treat dementias may need to be targeted to specific APOE genotypes.