The global genomic profile of hippocampal endothelial cells in fefemale diabetic mice is associated with cognitive dysfunction via alterations in cell adhesion and vascular permeability.
Type II diabetes mellitus (T2D) is a chronic metabolic disease, and a risk factor for cardiovascular disease and cerebrovascular dysfunction including vascular dementia. Sex differences in the prevalence of T2D, dementia, and global genomic changes in the brain have been observed; however, most studies have been performed in males exposing large knowledge gaps in females. Therefore, the aim of this study was to evaluate the consequence of T2D on cognitive function, and decipher underlying molecular transcriptomic mechanisms of endothelial cells in an important memory center, the hippocampus, in female diabetic mice. Adult female db/db and control wild type mice (n=10/group) were studied at age 18 weeks after which cognitive performance was assessed, metabolic parameters measured, and the hippocampus isolated for single nuclei RNA sequencing. db/db female mice exhibit characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared to female WT mice. Female db/db mice presented cognitive decline compared to wild type mice. snRNAseq showed that T2D induced significant change in the global transcriptome profile of hippocampal endothelial cells by modulating expression of not only protein coding genes but also lncRNAs.  These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization and cell adhesion, suggesting that diabetes increases endothelial cell permeability and therefore blood-brain permeability (BBB). Observed genomic changes also correlated with clinical Alzheimer's and vascular dementia. In conclusion, T2D, by multiomic transcriptional and post transcriptional regulation, modulates the expression of genes in brain endothelial cells, resulting in endothelial cell dysfunction predictive of increased BBB permeability, and negatively impacts cognitive function. Overall design: Wild type (C57BL/6J) and db/db female mice were fed a standard purified diet AIN-93M, for 8 wks. Mice were sacrificed at 18 weeks of age and hippocampus was dissected from left hemisphere and then stored at -80 degree celcius. Hippocampal nuclei was isolated and single nuclei RNA sequencing was performed. Brain hippocampal endothelial cells gene expression was analyzed using a multiomic approach for differential expression of protein and non-protein coding genes, gene networks, functional pathways, and transcription factors. Functional outcomes such as cognitive behavior and blood brain barrier permeability were also assessed.