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snRNAseq reveals hippocampal endothelial dysfunction in diabetic mice

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Type 2 diabetes (T2D) is a known risk factor for cerebrovascular diseases including Alzheimer's disease (AD), and vascular dementia (VaD). Yet, our understanding of the mechanisms whereby T2D contributes to neurodegeneration and VaD remains poorly defined. In this present work, we utilized the db/db murine model of T2D and single nuclei RNA sequencing to determine the effect of T2D on endothelial cell-specific transcriptomic changes in the hippocampus, an important brain memory center.
Through integrative multiomics, we demonstrate that T2D results in complex regulation of hippocampal endothelial cell function both at the transcriptional and post transcriptional levels through protein coding genes, transcription factors, and potential regulation via long noncoding RNAs. The transcriptomics exhibited a pattern reflective of T2D-associated endothelial cell function and signaling disruption, impaired permeability, neuroinflammation, and neurodegeneration. The complex and substantial multilevel genomic impact of T2D on the hippocampal endothelium we uncovered could help explain how T2D contributes to the endothelial functional dysregulation that characterizes AD and VaD.

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Saivageethi Nuthikattu, PhD

UC Davis

Assistant Project Scientist