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Publication
Single Nuclei Transcriptomics Reveals Obesity-Induced Endothelial and
Neurovascular Dysfunction: Implications for Cognitive Decline.
Authors Milenkovic D, Nuthikattu S, Norman JE, Villablanca AC
Submitted By Submitted Externally on 2/7/2025
Status Published
Journal International journal of molecular sciences
Year 2024
Date Published 10/1/2024
Volume : Pages 25 : Not Specified
PubMed Reference 39456952
Abstract Obesity confers risk for cardiovascular disease and vascular dementia. However,
genomic alterations modulated by obesity in endothelial cells in the brain and
their relationship to other neurovascular unit (NVU) cells are unknown. We
performed single nuclei RNA sequencing (snRNAseq) of the NVU (endothelial cells,
astrocytes, microglia, and neurons) from the hippocampus of obese (ob/ob) and
wild-type (WT) male mice to characterize obesity-induced transcriptomic changes
in a key brain memory center and assessed blood-brain barrier permeability (BBB)
by gadolinium-enhanced magnetic resonance imaging (MRI). Ob/ob mice displayed
obesity, hyperinsulinemia, and impaired glucose tolerance. snRNAseq profiled 14
distinct cell types and 32 clusters within the hippocampus of ob/ob and WT mice
and uncovered differentially expressed genes (DEGs) in all NVU cell types,
namely, 4462 in neurons, 1386 in astrocytes, 125 in endothelial cells, and 154
in microglia. Gene ontology analysis identified important biological processes
such as angiogenesis in endothelial cells and synaptic trafficking in neurons.
Cellular pathway analysis included focal adhesion and insulin signaling, which
were common to all NVU cell types. Correlation analysis revealed significant
positive correlations between endothelial cells and other NVU cell types.
Differentially expressed long non-coding RNAs (lncRNAs) were observed in cells
of the NVU-affecting pathways such as TNF and mTOR. BBB permeability showed a
trend toward increased signal intensity in ob/ob mice. Taken together, our study
provides in-depth insight into the molecular mechanisms underlying cognitive
dysfunction in obesity and may have implications for therapeutic gene targeting.




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