Cell- and sex-specificity in the transcriptomic response of the hippocampal neurovascular unit to obesity

Abstract Obesity is a risk factor for vascular dementia and exhibits sex differences in comorbidities and prevalence. However, its cell-specific effects on the neurovascular unit (NVU) remain unknown. Here we show, using the ob/ob mouse model and single nuclei RNA sequencing, how obesity modulates the hippocampal NVU transcriptome in females. Obesity alters endothelial-specific differentially expressed genes (DEGs) involved in angiogenesis and blood brain barrier permeability. DEGs in common between endothelial cells and other NVU cells are associated with neurotransmission and autophagy. Some gene expression changes from each NVU cell type correlate with behavioral changes. Sex-based analyses comparing to our previously reported male data indicate that the NVU transcriptomic response to obesity is modified by sex in a cell-type specific manner. Endothelial and microglial cells exhibit greater sex-specificity than astrocytes and neurons. The findings from our work may help inform both sex-independent and sex-specific approaches to prevention and treatment for obesity-related dementia.