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2019 Alzheimer's Association Research Grant (AARG)

Unravelling a novel mechanism favoring brain insulin resistance development

Could activating a protein that controls insulin help prevent Alzheimer’s brain changes?

Eugenio Barone, Ph.D.
Sapienza University of Rome
Rome, Italy


Insulin is a hormone that helps the body maintain appropriate levels of blood sugar.  Insulin can also be transported to the brain, where it helps maintain nerve cell energy levels and connections between nerve cells.  Since insulin plays an important role in the brain, researchers believe insulin might also play a role in Alzheimer’s progression.
Past studies show that problems with how insulin sends signals in the brain also known as “insulin resistance”, could lead to changes in nerve cell networks and cause cognitive symptoms of Alzheimer’s. Dr. Eugenio Barone has identified a protein that, when reduced, contributes to insulin resistance in the brain. This protein is called biliverdin reductase A, or BVR-A. Previous studies by Dr. Barone have shown BVR-A is reduced in the brain during Alzheimer’s and mild cognitive impairment, a condition with subtle memory loss that might precede dementia, including Alzheimer’s dementia.

Research Plan

Dr. Barone will use genetically-engineered mice susceptible to diabetes to examine how BVR-A contributes to insulin resistance and symptoms of Alzheimer’s. Dr. Barone’s team will feed mice a high-fat diet that favors development of insulin resistance in the brain, and ultimately, Alzheimer’s-like symptoms. The researchers will feed mice the high fat diet for up to 12 weeks, and measure how levels of BVR-A and other proteins involved in insulin resistance change over time. They will monitor how changes in these protein levels relate to development of insulin resistance and behavioral changes in the mice. Dr. Barone’s goal is to define when changes in BVR-A levels occur over the course of Alzheimer’s progression and its contribution to brain insulin resistance.
Dr. Barone’s team will also genetically engineer mice to lack BVR-A in their brains. Dr. Barone believes mice without BVR-A in their brains may experience worse insulin resistance and Alzheimer’s-like brain changes as compared to mice with normal BVR-A levels. In the second portion of the study, the researchers will treat mice on the high-fat diet with a small protein that activates BVR-A. They will determine whether this therapeutic approach can help prevent insulin resistance and symptoms of Alzheimer’s in these mice.


BVR-A could represent a new biological marker (biomarker) to predict insulin resistance in the brain, a risk for making brain more vulnerable to Alzheimer’s. It may also serve as early marker of Alzheimer’s related brain changes. Further, this study could help clarify the role of BVR-A, and whether adjusting its levels could represent a new therapeutic approach to prevent brain changes associated with Alzheimer’s.

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