(P29-020-24) Hippocampal Endothelial and Neurovascular Single Cell Transcriptomics in Obesity

Objectives: 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, 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 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  from the hippocampus of ob/ob mice.

Methods: 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 snRNAseq and data analyzed using in-dept bioinformatic analyses.

Results: 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 in astrocytes, 125 in endothelial cells, and 155 in microglia cells, suggesting that obesity 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.

Conclusions: Taken together, obesity exert significant cell-specific changes in global gene expression, genes that are associated with development of Alzheimer’s disease or dementia.

Funding Sources: This work was funded in part or in whole by the UCDavis Center for Women's Cardiovascular and Brain Health and the HEAL-HER (Heart, BrEast and BrAin Heath Equity Research) Program supported by residual class settlement funds in the matter of April Krueger v. Wyeth, Inc., Case No. 03-cv-2496 (US District Court, SD of Calif.)