MSU Pharmacology and Toxicology researchers using NHLBI grant to explore a potential dementia therapy

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Research has established connections between obesity and chronic conditions like heart disease and high blood pressure. Two Michigan State University scientists are now using a four-year, $2 million grant from the National Heart, Lung and Blood Institute to better understand the link between obesity and dementia, they will test if an existing FDA approved drug might slow the cognitive decline associated with dementia.

Anne Dorrance, an associate professor, and William Jackson, professor, both in the Department of Pharmacology and Toxicology, are exploring why people who are overweight or obese develop dementia at a faster rate than their lean peers. To do this they have developed a rodent model of life long obesity.

“It seems that your weight when you’re 70 or 80 and dementia is developing is not important, but your weight as you go through middle age is,” Dorrance says. “If you are obese though middle age something happens that sets your brain on a trajectory to develop dementia; we think being overweight changes how the arteries in the brain contract and dilate, this in turn changes how much blood flow and therefore energy the brain receives.”

They are using their specially developed rat model to examine the changes in cerebral arteries that occur with obesity. In the obese model, the cerebral arteries don’t dilate in the same way as they do in a lean rat, which can mean a decreased blood flow, impaired neuron function and memory development.

“One of the things we know about the obese population is that their cerebral blood flow is lower than non-obese patients, and it appears that their ability to increase blood flow to active regions of the brain is impaired” said Dorrance.

The question is why the dilation diminishes and how can it be treated?

“What we’re trying to understand in the grant is what makes that vasodilation go away - what makes the arteries not work correctly?” Jackson said. 

The two are looking at aldosterone, a hormone produced by the adrenal gland. It’s been implicated in cardiovascular disease, especially in patients who have high blood pressure, but obese people have higher circulating levels of aldosterone, whether or not they are hypertensive.

In previous work, Dorrance and Jackson have shown that by blocking the aldosterone receptor, they can improve the structure and the function of the brain’s blood vessels in hypertensive models.

“What we are hoping to show is that the same thing is true in the obese model -- if we treat the obese rats with a drug that blocks the actions of aldosterone we’ll get better dilation,” Dorrance noted. “We’ll be able to look at behavioral and cognitive deficits and see whether the drug works.”

The drugs that Dorrance and Jackson are using in the study are FDA-approved, which means there will be no development time or costs, and prescribers will already be familiar with them. 

“We’re looking at drugs that were developed and approved some time ago, so they are no longer patented and are available as generics, therefore they are less expensive,” Jackson added.

Though they expect that their findings may lead to therapies that can slow the progression of dementia, Dorrance and Jackson don’t expect that the treatments will reverse any neuron damage that has been done. 

“While the adult human brain can generate new neurons, it has a relatively limited capacity in a lot of its regions,” Jackson notes, “our goal is to stop the damage before that happens.”