Garceau, D. T. | Search bioRxiv

bioRxiv2022

APOEϵ4 and exercise interact to influence systemic and cerebral risk factors for dementia

INTRODUCTIONAPOE{varepsilon}4 is the strongest genetic risk factor for Alzheimers disease and related dementias (ADRDs) affecting many different pathways that lead to cognitive decline. Exercise is one of the most widely proposed prevention, and intervention strategies to mitigate risk and symptomology of ADRDs. Importantly, exercise and APOE{varepsilon}4 affect similar processes on the body and brain. While both APOE{varepsilon}4, and exercise have been studied extensively, their interactive effects are not well understood. METHODSTo address this, male and female APOE{varepsilon}3/{varepsilon}3, APOE{varepsilon}3/{varepsilon}4 and APOE{varepsilon}4/{varepsilon}4 mice ran voluntarily from wean (1mo) to midlife (12mo). Longitudinal and cross-sectional phenotyping was performed on the periphery and the brain, on markers of risk for dementia such as weight, body composition, circulating cholesterol composition, activities of daily living, energy expenditure, and cortical and hippocampal transcriptional profiling. RESULTSData revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum LDL concentration dependent on APOE genotype. Additionally, murine activities of daily living and energy expenditure were significantly influenced by an interaction between APOE genotype and running in both sexes. Transcriptional profiling of the cortex and hippocampus predicted that APOE genotype and running interact to affect numerous biological processes including vascular integrity, synaptic/neuronal health, cell motility, and mitochondrial metabolism, in a sex-specific manner. DISCUSSIONThese data provide compelling evidence that APOE genotype should be considered for population-based strategies that incorporate exercise to prevent ADRDs.

genetics↗

bioRxiv2020

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

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.

genomics↗