Single nuclei transcriptomics reveals altered endothelial cell function, permeability, and cognition in diabetic mice.

Diabetes (DM) increases cardiovascular and cerebrovascular disease risk. However, the mechanism of DM-associated microvascular dysfunction and neuroinflammation remain unknown. We present a global assessment of endothelial cell-specific gene expression and integrated transcriptomics directly addressing hippocampal endothelium in diabetic mice, with the goal of determining the effect of DM in endothelial cell function and potential implications to vascular dementia. We observe for the first-time differential gene expression with strong signatures of cell signaling, activation of pathways for endothelial dysfunction, and neurodegeneration. Moreover, we identified that the integrated transcriptomic changes associate with blood brain barrier disruption by magnetic resonance imaging, and behavioral alterations, and correlate with the clinical gene profile of dementia patients, revealing opportunities for treatments with specificity for molecular pathology. Overall design: Wild type (C57BL/6J) and db/db male 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.