Global Genomic Profile of Hippocampal Endothelial cells by single nuclei RNA sequencing in Female Diabetic Mice is Associated with Cognitive Dysfunction

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. Therefore, our aim was to evaluate the consequence of T2D on cognitive function and decipher the underlying molecular transcriptomic mechanisms of endothelial cells in an important brain memory center, the hippocampus, utilizing a female murine diabetes model. We assessed cognitive function, metabolic parameters, and then performed hippocampal single nuclei RNA sequencing (snRNA seq) in adult female db/db and control wild type mice. db/db mice exhibited characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared to WT mice. Female db/db mice presented cognitive decline compared to wild type mice, as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced significant changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long non-coding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization, and cell adhesion, suggesting that diabetes increases endothelial cell permeability. Observed genomic changes also correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia. In conclusion, T2D, by transcriptional and post-transcriptional regulation, regulates endothelial cell dysfunction predictive of increased vascular permeability, and negatively impacts cognitive function. Our work has implications for sex-specific molecular therapeutic targets for dementia in females.