Although strokes can occur no matter how old you are, your risk for one increases as you age. About two-thirds of the people hospitalized for one are at least 65 years old, according to the Centers for Disease Control. Yet historically, most stroke studies involving animal models have focused on young test subjects, not older ones.
“That doesn’t really mimic the person who gets a stroke,” said Candice Brown, a researcher with the West Virginia University School of Medicine and Rockefeller Neuroscience Institute. “You’ve got to use older models. It’s more rigorous and translates better to the real world.”
To fill this knowledge gap, Brown and her colleagues are exploring how a specific enzyme protects the brain from the effects of stroke and aging. What they learn could indicate a potential target for medications that improve how the brain’s blood vessels function after a stroke. Their findings could even point to therapeutics for other age-related disorders.
The National Institute on Aging—a division of the National Institutes of Health—is awarding WVU $2,687,415 for the five-year project.
The project builds on previous research that Brown and her colleagues conducted into a different disease model: sepsis. Their earlier work showed that sepsis caused a certain enzyme—called “tissue-nonspecific alkaline phosphatase,” or TNAP—to decline after injury in the brains of animal models.
“I knew that something was up,” Brown said. “I knew that there was a decrease in the enzyme activity, but it wasn't due to a loss of the blood vessels. So, that was really intriguing to me.”
This time, Brown and her team aren’t observing the effects of sepsis on the brain. They’re using animal models to see how TNAP influences the brain’s response to a stroke.
TNAP is important because it protects the tiny blood vessels that permeate the brain. It also helps to preserve the blood brain barrier, which keeps toxins and pathogens from infiltrating the brain. But scientists don’t yet understand the mechanism behind how it works.
“This enzyme is present in every cell,” Brown said. “The scientific community has known that it’s present in cells for almost a century. We’ve known that its function is to remove phosphorus from toxins or other pathogens. And—for some reason that people don't understand—we’ve known that there’s a lot of this enzyme activity in the blood vessels of the brain. But we don’t really know understand why.”
She and her colleagues will genetically modify some of the models so that a particular type of brain cell can’t make TNAP anymore. Another group of models will keep their TNAP function intact.
By combining live imaging and measuring brain inflammation, the researchers will observe how the brains of animals in both groups heal from stroke over time. They’ll also assess the post-stroke behavior of animal models in the two groups. For example, does one group tend to move faster than the other, walk in a straighter line or navigate a maze better?
What they discover will shed light on the role that TNAP plays in maintaining and restoring brain health.
“Some cells die during a stroke,” Brown said. “These cells are found in the core of the infarct and cannot be saved. The injured cells around the core are called the penumbra, and they can be saved if the brain is able to respond appropriately. We think the TNAP in brain blood vessels may help to prevent cell loss or promote recovery after stroke. That’s another aspect that we want to understand about what is occurring after the stroke. These studies will tell us if this gene is important and what the long-term implications are of having this gene disrupted in in brain blood vessels.”
In addition, the team will see how young and old animal models fare. Some of those models will have experienced stroke; others, which will serve as healthy controls, won’t.
To make the study more translationally relevant, they’ll also test for differences between males and females.
“We know the enzyme function decreases after injury—after the stroke or sepsis—but we also want to know if the loss of enzyme function is also associated with general brain aging,” Brown said. “With this grant, we said, ‘Let’s test this in stroke, and then let’s test this in aging. And then, also, let’s test this in models that are older versus models that are younger that also have a stroke.”
Learning more about the basic biology of TNAP is critical because therapeutics for stroke are scarce. In fact, the Food and Drug Administration has approved just one drug to treat stroke: tissue plasminogen activator, or tPA. And doctors have to administer it within six hours of the stroke’s onset.
“If you miss that window, you cannot receive the drug,” Brown said.
“With the exception of tPA, there have been hundreds, if not thousands, of drugs that have been tested in rodents for stroke that have been shown to decrease cell death and, in some cases, improve motor function,” she said. “But when the drugs are tested in human clinical trials, they fail miserably. This has been a problem in stroke research for a very long time. So, we’re comparing the results in young mice versus much older mice that would mimic perhaps a 60-to-70-year-old individual.”
Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health, under Award Number 1R01AG068155. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH.
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