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Fighting Alzheimer’s


Combating a Cruel Killer: Science Professors Join Forces to Fight Alzheimer’s Disease

by Robyn Ross
 
Alzheimer’s disease steals its victims’ memories and robs their families of invaluable time with loved ones. On a national scale, the brain disease gobbles more than $220 billion each year just in caregiving costs. 
 
Of the six leading causes of death in the U.S., the neurodegenerative disease is the only one rising; it claims about 500,000 lives a year. 
Three professors in TCU’s College of Science and Engineering are using the tools of their respective academic disciplines to research the disease. Associate professor of biology Michael Chumley, assistant professor of chemistry Kayla Green and associate professor of psychology Gary Boehm formed the Neurobiology of Aging Collaborative to study the amyloid beta proteins associated with Alzheimer’s disease -- how they form and impair cognition as well as how that formation process might be interrupted.
 
Two of the pathological hallmarks of Azheimer’s disease are the formation of plaques in the brain, primarily made of aggregations of a protein called amyloid beta, and the cognitive dysfunction that results. Everyone makes amyloid beta, but in healthy people, the brain’s glymphatic system clears the protein. In people with Alzheimer’s disease, the protein accumulates and eventually forms plaques. Amyloid plaque buildup is a slow process, taking many years as the disease develops. The formation of the plaques may begin in a person’s 30s, while symptoms of the disease won’t appear for decades. 
 
Green, a synthetic inorganic chemist, studies the transition metal ions and their role in biological processes. She said that scientists need to understand the processes happening at the molecular level to know “what we’re up against” in trying to prevent disease. Metals are necessary for functions such as energy production and muscle growth, but they can play a role in the development of disease. When interacting with amyloid beta, for example, metals can contribute to the production of oxidative stress, which can kill neurons and synapses responsible for learning and memory. 
 
Green wanted to investigate the conditions that would make the metals use their powers for good instead of evil. Working with students in her lab, the professor creates molecules designed to stop metal ions from causing oxidative stress by chaperoning them to their appropriate destination in the body. The molecular compounds, collectively called N-heterocyclic amines, include both an antioxidant and a component that binds to the metal ions. Together, they block the formation of amyloid beta and production of oxidative stress.
 
Green and her students test their work by combining the amyloid beta protein with a metal ion in a test tube, which causes the solution to get cloudy (mimicking the formation of plaque in the brain). Adding the molecules they have developed clears the solution and dissolves the amyloid beta. They also have been able to demonstrate through X-ray crystallography that the molecules they’ve created bind to metal ions. Green worked with associate professor of biology Giri Akkaraju to test the compounds in cellular models before teaming with Chumley and Boehm to experiment with the effects using mice. 
 
Chumley and Boehm’s lab differs from many others that do research on Alzheimer’s disease. Most labs use transgenic models, or mice genetically modified to exhibit the early-onset form of Alzheimer’s disease. But early-onset, or familial, Alzheimer’s represents less than 10 percent of all human cases of the disease. Why do the other 90 percent develop the disease? To research that question, the lab uses mice that haven’t been genetically modified. For unknown reasons, the lab mice exhibit elevated levels of amyloid beta, which impairs memory and learning, just as it does in humans.
 
One factor that can lead to excess amyloid beta production is inflammation. People with Alzheimer’s disease have a higher than normal incidence of chronic types of inflammatory diseases, such as rheumatoid arthritis and diabetes. Inflammation also is present in Alzheimer’s patients’ brains where plaques form. Following a line of inquiry from then-graduate student Marielle Weintraub, Chumley and his lab assistants examined the connection between inflammation and amyloid beta levels. They are trying to understand where and why the excess amyloid beta was produced.
 
Chumley wanted to see if repeated illness, such as bacterial or viral infections, set off the inflammation and amyloid beta production cycle in the brain. To research the idea, he injected a group of mice with a substance that induced a bacterial inflammation and another group with a compound that induced a viral inflammation. 
 
In both experiments, while the inflammation was peripheral (outside the brain), subsequent examination of the brain revealed elevated levels of amyloid beta. The question remained: Where was the amyloid beta coming from?
 
“And there’s two possibilities,” Chumley said. “Either it’s getting made in the periphery, and it’s getting transported in, or it’s being made in the brain.”
 
Chumley’s team continued causing the inflammatory reactions in mice but treated them with the anti-cancer drug Gleevec, which inhibits amyloid beta production outside the brain. Gleevec doesn’t cross the blood-brain barrier, confining its effects to the periphery. Chumley thought the drug would be a good instrument to test whether or not the amyloid beta was being made in the periphery.
 
If mice brains showed elevated levels of amyloid beta even when Gleevec was inhibiting its production in the periphery, the protein was being made in the brain. But if the mice brains didn’t show amyloid beta, Chumley could conclude that the inflammation responses were causing amyloid to be made in the periphery and then find its way to the brain. 
 
Research results showed that amyloid beta was being produced in the periphery and getting traveling into the brain. However, long-term use of Gleevec by humans is impractical. But if the oxidative stress associated with inflammation is preventable through other means, perhaps the peripheral production of amyloid beta also could be stopped another way. Thus, the team tested exercise as an alternative.
 
“We know that exercise reduces inflammation, and that individuals (who) are physically active have a lower incidence of Alzheimer’s disease,” Chumley said. 
 
Researchers induced inflammation in mice for a week, which increased the amyloid beta in their brains. Two weeks later, Chumley compared amyloid beta levels in the brains of mice that had access to a running wheel with those that were sedentary. The mice with running wheels in their cages completely eliminated the amyloid beta, suggesting exercise is an effective defense against buildup. Now the research team is trying to figure out how that process works.
 
“If you cause inflammation in the mouse, it leads to amyloid buildup in the brain and the learning dysfunction -- and it doesn’t matter how you cause the inflammation, whether it’s bacterial or viral,” Chumley said. “If you have the inflammation, but you block the production of amyloid beta, it doesn’t get in the brain, and the mice learn just fine. This is the really early stage of a potential model that suggests if you get sick, it can lead to an increase in amyloid beta production, which may end up in your brain.”
 
Boehm, a behavioral neuroscientist, studies the cognitive dysfunction that results from these aberrant biological processes. In the lab, Boehm assessed the effects of inflammation on memory function in mice by studying how well they were able to remember a novel context that had been paired with a mildly aversive stimulus. To test this inquiry, mice were removed from their normal cages and placed in a chamber that had new features: a different spatial configuration, polka dots on the walls, a different kind of floor and the scent of peppermint oil. This new context was paired briefly with a mildly aversive stimulus.
 
After only a couple of pairings, mice normally learned the connection between the two and froze when placed in the new environment, even in the absence of the aversive stimulus. But mice in which peripheral inflammation was induced froze far less, suggesting they were less able to remember the connection between the novel environment and the unpleasant stimulus. These observations confirmed the connection between amyloid beta -- elevated because of the inflammation -- and cognitive dysfunction in non-transgenic mice.
 
Mice treated with the drug, Gleevec, on the other hand, were able to learn the connection between the new environment and the aversive stimulus even when inflammation was triggered. This research outcome suggests Gleevec could protect against amyloid beta buildup as well as rescue cognitive function. Boehm and his research team now are assessing whether exercise yields a similar protective effect. 



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