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Effect of obesity on the neurovascular unit transcriptome in the female mice hippocampus using single nuclei RNA seq

ABSTRACT: Obesity is a global pandemic and a key risk factor for several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease, or dementia. The neurovascular unit (NVU), essential for blood-brain barrier (BBB) integrity and comprised of endothelial cells, glial cells (microglia and astrocytes), and neurons, plays an important role in the pathogenesis of neurodegenerative diseases. However, molecular mechanisms underlying the effects of obesity on endothelial and other cells of and its contribution to neurodegeneration remains largely unknown, especially in females. In this study we aimed to decipher in-dept molecular modifications induced by obesity in cells of neurovascular unit by integrative multiomics analysis of endothelial cells, neurons, microglial cells, and astrocytes from the hippocampus of ob/ob female mice. Hippocampus were isolated from ob/ob and C57BL/6J female mice at 17-18 weeks of age. Gene expression profiles of cells of hippocampus were obtained using single nuclei RNA sequencing (snRNAseq) and data analyzed using in-depth bioinformatic analyses.

ORGANISM(S): Mus musculus

PROVIDER: GSE263863 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:Obesity is a global pandemic and a key risk factor for several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease, or dementia. The neurovascular unit (NVU), essential for blood-brain barrier (BBB) integrity and comprised of endothelial cells, glial cells (microglia and astrocytes), and neurons, plays an important role in the pathogenesis of neurodegenerative diseases. However, molecular mechanisms underlying the effects of obesity on endothelial and other cells of and its contribution to neurodegeneration remains largely unknown. In this study we aimed to decipher in-dept molecular modifications induced by obesity in cells of neurovascular unit by integrative multiomics analysis of endothelial cells, neurons, microglial cells, and astrocytes from the hippocampus of ob/ob mice. Hippocampus were isolated from ob/ob and C57BL/6J male mice at 17-18 weeks of age. Gene expression profiles of cells of hippocampus were obtained using single nuclei RNA sequencing (snRNAseq) and data analyzed using in-dept bioinformatic analyses. snRNAseq and UMAP analysis revealed 19 cell types in hippocampus. Comparisons of global gene expression profiles identified different global profiles between ob/ob and WT for each of the cell types of the NVU. Statistical analyses revealed 4463 DEGs in neuronal cells, 1386 DEGs in astrocytes, 125DEGs in endothelial cells, and 155 DEGs in microglia cells, suggesting that obesity significantly impacts the expression profiles of NUV cells. Enrichment analyses revealed that these genes are involved in cellular processing like focal adhesion, cell interactions, inflammation, and metabolism. Changes in the expression in endothelial cells were positively correlated with genomic changes in other cell types, changes that we correlated with tendency in increase in BBB observed using functional MRI. Taken together, obesity exert significant cell-specific changes in global gene expression, genes that are associated with development of Alzheimer’s disease or dementia.

Project description:The neurovascular unit (NVU) is a complex multicellular structure that helps maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. While extensive evidence links NVU alterations to cerebrovascular diseases and neurodegeneration, the underlying molecular mechanisms remain unclear. Here, we use zebrafish embryos carrying a mutation in Scavenger Receptor B2, a highly conserved endolysosomal protein expressed predominantly in Radial Glia Cells (RGCs), to investigate the interplay among different NVU components. Through live imaging and genetic manipulations, we demonstrate that compromised acidification of the endolysosomal compartment in mutant RGCs leads to impaired Notch3 signaling, thereby inducing excessive neurogenesis and reduced glial differentiation. We further demonstrate that alterations to the neuron/glia balance result in impaired VEGF and Wnt signaling, leading to severe vascular defects, hemorrhages, and a leaky BBB. Altogether, our findings provide novel insights into NVU formation and function and offer new avenues for investigating diseases involving white matter defects and vascular abnormalities. The neurovascular unit (NVU) is a complex multicellular structure that helps maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. While extensive evidence links NVU alterations to cerebrovascular diseases and neurodegeneration, the underlying molecular mechanisms remain unclear. Here, we use zebrafish embryos carrying a mutation in Scavenger Receptor B2, a highly conserved endolysosomal protein expressed predominantly in Radial Glia Cells (RGCs), to investigate the interplay among different NVU components. Through live imaging and genetic manipulations, we demonstrate that compromised acidification of the endolysosomal compartment in mutant RGCs leads to impaired Notch3 signaling, thereby inducing excessive neurogenesis and reduced glial differentiation. We further demonstrate that alterations to the neuron/glia balance result in impaired VEGF and Wnt signaling, leading to severe vascular defects, hemorrhages, and a leaky BBB. Altogether, our findings provide novel insights into NVU formation and function and offer new avenues for investigating diseases involving white matter defects and vascular abnormalities. The neurovascular unit (NVU) is a complex multicellular structure that helps maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. While extensive evidence links NVU alterations to cerebrovascular diseases and neurodegeneration, the underlying molecular mechanisms remain unclear. Here, we use zebrafish embryos carrying a mutation in Scavenger Receptor B2, a highly conserved endolysosomal protein expressed predominantly in Radial Glia Cells (RGCs), to investigate the interplay among different NVU components. Through live imaging and genetic manipulations, we demonstrate that compromised acidification of the endolysosomal compartment in mutant RGCs leads to impaired Notch3 signaling, thereby inducing excessive neurogenesis and reduced glial differentiation. We further demonstrate that alterations to the neuron/glia balance result in impaired VEGF and Wnt signaling, leading to severe vascular defects, hemorrhages, and a leaky BBB. Altogether, our findings provide novel insights into NVU formation and function and offer new avenues for investigating diseases involving white matter defects and vascular abnormalities.

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Effect of obesity on the neurovascular unit transcriptome in the female mice hippocampus using single nuclei RNA seq

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