Mechanisms of Cognitive Decline Associated with Diabetes
People living with Type 2 diabetes are at increased risk for cognitive decline and Alzheimer’s disease. Our research uses both cell and animal models to study the impact of diabetes on the brain. In particular, we are interested in:
- How insulin regulates cholesterol synthesis in the different cell types of the brain and how this impacts brain energetics and function.
- The potential role of oxidized cholesterol species as signaling molecules in the brain in diabetes and Alzheimer’s disease.
- Understanding the role of insulin in the pathogenesis of Alzheimer’s disease.
Cholesterol metabolism in the brain is unique from the periphery. Cholesterol is unable to cross the blood brain barrier so the brain produces its own supply. In addition, the blood brain barrier regulates insulin access to the brain. Insulin receptor activation contributes to the synthesis of brain cholesterol. It has been observed that in the diabetic mouse there is an impairment of cholesterol synthesis and this is mediated by insulin deficiency. We have followed up on these studies, knocking out the key transcriptional regulator of cholesterol, SREBP2, in the main cholesterol synthesizing cells of the brain, the astrocytes.
We find that loss of cholesterol synthesis by astrocytes leads to an increase in brain glucose metabolism, resulting in altered whole body metabolism in the animals. In addition, alterations in brain lipid oxidation result in circadian rhythm disruptions. We are currently investigating the underlying mechanisms of these circadian rhythm disruptions as well as exploring altered cholesterol synthesis in other cells of the brain.
There are currently clinical trials using intranasal insulin to attempt to modify Alzheimer’s disease progression. The mechanisms that may be driving these changes are currently unclear. We are interested in better defining the targets of intranasal insulin with the thought that there may be more efficient or specific ways to activate the desired pathways for improved clinical outcome. These studies are being conducted using cell culture in combination with insulin receptor knockout and Alzheimer’s disease mouse models.
BIG Center hike in Shenandoah National Park, 2018.