Biology subjects

Foley, K. E.

Publications and source records attributed to Foley, K. E..

4 recordsLinked to original sources

bioRxiv2023

Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction

STRUCTURED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSAlzheimers disease (AD) is the most common cause of dementia worldwide, with apolipoprotein {varepsilon}4 (APOE{varepsilon}4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODSPET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTSAll hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOE{varepsilon}4/{varepsilon}4 exhibited significant Type-1 uncoupling ({downarrow} glucose uptake, {uparrow} perfusion) at 8 and 12 mo, while APOE{varepsilon}3/{varepsilon}4 demonstrated Type-2 uncoupling ({uparrow} glucose uptake, {downarrow} perfusion), while immunopathology confirmed cell specific contributions. DISCUSSIONThis work highlights APOE{varepsilon}4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.

neuroscience↗

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↗

bioRxiv2019

Transcriptional profiling reveals running promotes cerebrovascular remodeling in young but not aged mice

BackgroundThe incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimers disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood.\n\nResultsTo better understand the effects of exercise, we preformed transcriptional profiling on young (1-2 months) and midlife (12 months) C57BL/6J (B6) male mice after 12 weeks of voluntary running. Data was compared to age-matched sedentary controls. Interestingly, the midlife running group naturally broke into two cohorts based on distance ran - either running a lot and more intensely (high runners) or running less and less intensely (low runners). Midlife high runners had lower LDL cholesterol as well as lower adiposity (%fat) compared to sedentary, than midlife low runners compared to sedentary suggesting more intense running lowered systemic markers of risk for age-related diseases including dementias. Differential gene analysis of transcriptional profiles generated from the cortex and hippocampus showed thousands of differentially expressed (DE) genes when comparing young runners to sedentary controls. However, only a few hundred genes were DE comparing either midlife high runners or midlife low runners to midlife sedentary controls. This indicates that, in our study, the effects of running are reduced through aging. Gene set enrichment analyses identified enrichment of genes involved in extracellular matrix (ECM), vascular remodeling and angiogenesis in young runners but not midlife runners. These genes are known to be expressed in multiple vascular-related cell types including astrocytes, endothelial cells, pericytes and smooth muscle cells.\n\nConclusionsTaken together these results suggest running may best serve as a preventative measure to reduce risk for cerebrovascular decline. Ultimately, this work shows that exercise may be more effective to prevent dementia if introduced at younger ages.

genomics↗