APOEε3/ε4 and APOEε4/ε4 genotypes drive unique gene signatures in the cortex of young mice

Abstract

BackgroundRestrictions on mouse models have significantly impacted research towards understanding the most common genotype contributing to dementia in the human population - APOE{varepsilon}3/{varepsilon}4. To address this, as part of MODEL-AD, we created new versions of humanized APOE{varepsilon}4 and APOE{varepsilon}3 mice on a C57BL/6J background that allow for unrestricted distribution and breeding. MethodsTo determine similarities and differences between APOE{varepsilon}3/{varepsilon}4 and APOE{varepsilon}4/{varepsilon}4 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{varepsilon}3/{varepsilon}4 and APOE{varepsilon}4/{varepsilon}4 to the reference APOE{varepsilon}3/{varepsilon}3. To further compare APOE genotypes, cohorts of APOE{varepsilon}3/{varepsilon}3, APOE{varepsilon}3/{varepsilon}4, and APOE{varepsilon}4/{varepsilon}4 mice were exercised by voluntary running from 1 month to 4 months of age. ResultsCholesterol 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{varepsilon}3/{varepsilon}4 genotype showed unique transcriptomic signatures to that of APOE{varepsilon}4/{varepsilon}4. Functional enrichment of the APOE{varepsilon}3/{varepsilon}4, but not APOE{varepsilon}3/{varepsilon}4 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{varepsilon}3/{varepsilon}4 but not APOE{varepsilon}4/{varepsilon}4 genotype. WGCNA analysis confirmed findings from linear modeling but also predicted that running at a young age affects myelination and gliogenesis across APOE genotypes. ConclusionsIn summary, APOE{varepsilon}3/{varepsilon}4 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.