Single nuclei transcriptomics in diabetic mice reveals altered brain hippocampal endothelial cell function,...

Area of Science:

• Neuroscience
• Genomics
• Endocrinology

Background:

• Type 2 diabetes mellitus (T2DM) is linked to cognitive impairment, but the underlying molecular mechanisms in the brain remain unclear.
• Gene dysregulation in brain endothelial cells (EC) may contribute to T2DM-related dementia.
• Understanding these changes is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate gene expression changes in the hippocampus of T2DM mice.
• To identify molecular pathways and regulatory factors involved in T2DM-induced brain endothelial dysfunction.
• To correlate murine findings with human dementia datasets (Alzheimer's disease and vascular dementia).

Main Methods:

• Single nuclei RNA sequencing of hippocampal EC from db/db mice (T2DM model) and wild-type controls.
• Gadolinium-enhanced MRI to assess blood-brain barrier (BBB) permeability.
• Integration of murine transcriptomic data with human AD and VaD gene expression profiles.
• Cognitive behavioral assessments.

Main Results:

• Significant differences in the transcriptome of diabetic hippocampal EC compared to controls.
• Enrichment of pathways related to EC signaling, neuroinflammation, BBB disruption, and neurodegeneration.
• MRI confirmed BBB dysfunction linked to endothelial molecular alterations.
• Diabetic EC transcriptome positively correlated with gene expression in human AD and VaD.

Conclusions:

• T2DM induces significant gene dysregulation in brain endothelial cells, contributing to neuroinflammation and BBB disruption.
• These endothelial changes are implicated in cognitive decline associated with T2DM.
• Findings suggest potential endothelial-specific therapeutic targets for T2DM-related cognitive impairment.