| First Author | Foley KE | Year | 2021 |
| Journal | bioRxiv | Mgi Jnum | J:300626 |
| Mgi Id | MGI:6504008 | Doi | 10.1101/2020.10.28.359422 |
| Citation | Foley KE, et al. (2021) APOEepisilon3/epsilon4 and APOEepsilon4/epsilon4 genotypes drive unique gene signatures in the cortex of young mice. bioRxiv |
| abstractText | Restrictions on mouse models have significantly impacted research towards understanding the most common genotype contributing to dementia in the human population â APOEe3/e4. To address this, as part of MODEL-AD, we created new versions of humanized APOEε4 and APOEe3 mice on a C57BL/6J background that allow for unrestricted distribution and breeding. Methods: To determine similarities and differences between APOEe3/e4 and APOEe4/e4 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 APOEe3/e4 and APOEe4/e4 to the reference APOEe3/e3. To further compare APOE genotypes, cohorts of APOEe3/e3, APOEe3/e4, and APOEe4/e4 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 APOEe3/e4 genotype showed unique transcriptomic signatures to that 41 of APOEe4/e4. Functional enrichment of the APOEe3/e4, but not APOEε3/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 APOEe3/e4 but not APOEe4/e4 genotype. WGCNA analysis confirmed findings from linear modeling but also predicted that running at a young age 46 affects myelination and gliogenesis across APOE genotypes. |
