An integrated experimental and computational model of brain microvascular endothelial cell glucose metabolism and transport

University Of Maryland, College Park, College Park MD

Investigators

Abstract

Alzheimer’s disease may be partially caused by changes in brain blood vessels. People who have both low and high blood cholesterol are at increased risk of developing Alzheimer’s disease. However, it is not clear how blood cholesterol affects brain blood vessels. Early studies suggest that low cholesterol causes cells in brain blood vessels to use more sugar, which means that they pass less sugar on to the brain. Since low sugar in the brain is also a sign of Alzheimer’s disease, it is possible that changes in brain blood vessels due to low cholesterol may contribute to Alzheimer's disease by lowering brain sugar levels. In this research, the investigators will conduct experiments and analyze their results using computer models to learn how cholesterol changes the way that brain blood vessels pass sugar into the brain. The investigators will also engage undergraduate students to do research in their laboratories, and the investigators will teach local high school students about brain blood vessels, cholesterol, and Alzheimer’s disease. This project will create new methods to study Alzheimer’s disease and could lead to new drugs to treat early Alzheimer’s disease. Glucose metabolism is reduced in the brains of patients with Alzheimer’s disease, perhaps due to reduced glucose transport by brain microvascular endothelial cells (BMEC). Endothelial cells such as BMEC become dysfunctional in conditions of altered blood metabolites, like cholesterol. The risk of Alzheimer’s disease increases with high cholesterol in mid-life yet also increases with low cholesterol later in life. It is therefore imperative to understand how both high and low cholesterol impact BMEC glucose transport. The investigator's experimental and computational analyses show that decreased membrane cholesterol causes BMEC to reduce glucose transport, increase glycolytic metabolism, upregulate cholesterol synthesis, and decrease mitochondrial metabolism. These data suggest that cholesterol-depleted BMEC shift their systemic metabolism. Therefore, the goal of this project is to investigate how decreased membrane cholesterol affects BMEC glucose metabolism and transport using integrated experimental and computational models. When completed, these studies will provide new experimental and computational models for studying integrated BMEC glucose metabolism and transport, as well as elucidate the mechanistic link between cholesterol and glucose transport to provide new insight into cholesterol and cholesterol-lowering therapies in neurodegenerative disease. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.