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

Author:

Foley Kate E.ORCID,Garceau Dylan T.,Kotredes Kevin P.,Carter Gregory W.ORCID,Sasner Michael,Howell Gareth R.ORCID

Abstract

AbstractBackgroundRestrictions on mouse models have significantly impacted research towards understanding the most common genotype contributing to dementia in the human population – APOEε3/ε4. To address this, as part of MODEL-AD, we created new versions of humanized APOEε4 and APOEε3 mice on a C57BL/6J background that allow for unrestricted distribution and breeding.MethodsTo determine similarities and differences between APOEε3/ε4 and APOEε4/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 APOEε3/ε4 and APOEε4/ε4 to the reference APOEε3/ε3. To further compare APOE genotypes, cohorts of APOEε3/ε3, APOEε3/ε4, and APOEε4/ε4 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 APOEε3/ε4 genotype showed unique transcriptomic signatures to that of APOEε4/ε4. Functional enrichment of the APOEε3/ε4, 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 APOEε3/ε4 but not APOEε4/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.ConclusionsIn summary, APOEε3/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.

Publisher

Cold Spring Harbor Laboratory

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