2022 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)

Cerebral Hypoperfusion Induces Insulin Resistance and Exacerbates AD

How can the regulation of sugar and blood flow impact nerve cell function in the brain?

Theresa Lansdell, Ph.D.
Michigan State University
East Lansing, MI - United States

Background

Blood vessels in the brain provide nerve cells with oxygen-rich blood that is necessary for the cells’ ability to function properly. Inadequate blood flow can damage and eventually kill cells anywhere in the body, but the brain is especially vulnerable. Studies show that loss of brain blood vessel (or cerebrovascular) function, which may occur with aging, may also be an early brain change in dementia. These changes may be associated with nerve cell damage and death observed in Alzheimer’s or other dementias. 

In addition to age, insulin resistance is another significant risk factor for dementia. Insulin is a hormone that helps the body maintain appropriate levels of blood sugar. Insulin is also transported into the brain, where it is important for helping nerve cells acquire and use the energy they need. Insulin resistance (IR) is a condition where insulin is not used effectively by the body’s cells. This could lead to high blood sugar levels that damage tissue and cause inflammation throughout the body, including the brain. 

Past studies have shown that IR could be associated with changes in brain cell networks and changes in memory and thinking observed in individuals with Alzheimer’s. As a result, individuals with IR may be at greater risk for developing dementia. However, the links between cerebrovascular disease, IR, and dementia are not well understood.

Research Plan

Dr. Theresa Lansdell and colleagues believe that reduced brain blood flow initiates a cycle of IR that is associated with nerve cell injury and cognitive decline. To test this, the researchers will reduce brain blood flow and induce IR in rats to study how this  impacts the dilation (enlargement) of specialized brain blood vessels (called cerebral parenchymal arterioles, critical blood vessels in the brain). They will also study the effects on nerve cell health. They will also conduct behavioral cognitive tests on the rats with insulin resistance to study the impact on memory. Finally, they will collect the brains of the rats to study specific cellular mechanisms under the microscope.  

To determine if reduced brain blood flow and IR contribute to the development of nerve cell injury and cognitive impairment, the team will treat rats with an insulin sensitizing drug to help control blood sugar levels in the rats. Following treatment, the rats will undergo behavioral testing before their brains are examined to see if reducing insulin resistance can stop nerve cell damage and other impairments.

Impact

Results from this project could shed new light on the role of insulin resistance in both dementia and aging. They could also lead to novel methods of diagnosing and treating brain disease.