Impact of obesity on neural vascular function

• Applicant: Bilal Sheikh, Ph.D.
• Subject Area: Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457240345

Mid-life obesity is associated with a significantly increased risk of neurodegeneration and cognitive decline in later years. However, the molecular changes responsible for this association remain unknown. Recent work is starting to uncover the unexpected key role of vascular dysfunction in the induction of neurodegeneration. Indeed, increased neural vascular dysfunction in cognitively normal humans correlates with increased risk of cognitive decline later in life.In addition to cognitive decline, obesity is also associated with an increased incidence of vascular disease. Consistently, our preliminary data has shown that neural vessels show increased permeability in obese mice, a well-established indicator of vascular dysfunction. Furthermore, our recent work has uncovered that changes in the neural metabolic profile directly impairs the function of neural vascular cells in vivo. Given the correlation between obesity and an abnormal metabolic environment, we hypothesize that obesity directly induces dysfunction of neural vascular cells, leading to a deregulated brain microenvironment and thereby promoting cognitive decline. We will investigate our hypothesis through state-of-the-art imaging, flow cytometry, single cell transcriptomics and single cell epigenetic techniques to identify how obesity impacts the function, transcriptional profile and epigenetic landscape of neural vascular endothelial and mural cells. Mouse models maintained on the high fat and high sugar “Western diet” will utilized for these experiments, as this is considered the most physiological model of obesity. Through our multidisciplinary and mechanistic experimental approach, our work will reveal the key molecular networks that are deregulated in neural vascular cells in response to obesity and identify potential therapeutic targets to reduce the risk of cognitive decline in high-risk individuals.

• DFG Programme: Research Grants