New Alzheimer Disease Study Makes Connection To Cause

Dealing with Alzheimer disease is one of the most frustrating, heartbreaking ordeals a family has to go through in life. And Alzheimer researchers have had their own level of frustration as well.
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Dealing with Alzheimer disease is one of the most frustrating, heartbreaking ordeals a family has to go through in life.

And Alzheimer researchers have had their own level of frustration as well. There are no viable therapies, so only 45 percent of patients are even told they have it, and it's proven to be one of the most complex disease there is. Scientists say they don't know very much when it onsets and don't have a designed mechanism of what the process of the disease is.

Could it be that all of that is about to change?

That's what researchers at the Duke Institute for Brain Sciences are hoping after their study shows the immune system, which is supposed to protect people, plays a role in Alzheimer's.

Carol Colton, a professor of neurology at the Duke University School of Medicine, says that a new study with mice suggests that certain immune cells that normally protect the brain begin to abnormally consume arginine, an important ingredient. Colton says using a small-molecule drug helped block this process and prevented brain plaques and memory loss in mice.

"If indeed arginine consumption is so important to the disease process, maybe we could block it and reverse the disease," says Colton, co-author of the study published in the Journal of Neuroscience.

Colton says working with Alzheimer disease has been pressure-filled for researchers because so many people are affected by it, forging a huge impact on society.

Everyone has been anxious to find a new direction and consider different concepts to deal with Alzheimer's, Colton says. That prompted her group to take another look and treat it like any other disease process in the body where there is an immune response.

Immunity is a big factor in all diseases, and it wasn't surprising that it plays a role in Alzheimer's, Colton says. The issue had long been pushed to the side, but when therapies weren't working, it was time to take a different direction.

Colton describes the brains of people with Alzheimer's disease as showing two hallmarks -- plaques and tangles -- that researchers have puzzled over for some time. Plaques are the buildup of sticky proteins called beta amyloid, and tangles are twisted strands of a protein called tau, Colton says.

Because researchers are trying to determine how Alzheimer's affects humans, Colton says the study used a mouse created several years ago in which the mouse immune system was made more similar to a human.

The mouse has behavior changes and neuron loss, and because the onset of the symptoms are gradual, it enables researchers to study the brain over time and see how the disease begins, Colton says.

"We said we want to go back in time and look at the very beginning of AD," Colton says. "Obviously, you can't do that in humans. When we did this study and made this mouse, what we did was go back way at the beginning of the disease process and look at what was going on in terms of the immune response from an early age to an older age where you clearly see the disease."

What researchers found is that the immune response was different than what anybody had predicted, Colton says. It wasn't "like an inferno" that a lot of people imagined.

Researchers look at the body's immune system as either a warrior or a nurturer, Colton says. The warrior phase in people is intended to kill bacteria and virus, and the nurturer phase is after the attack has happened and helps to recover and promote survival.

"It's easy to see how the warrior phase would kill," Colton says. "It's not easy to see how the nurturer phase would."

The immune system is smart and uses anything to allow us to survive, Colton says. What researchers found in the early stage of the mouse model is that the nurturer phase was turned on.

"It makes sense because we're getting a disease process started, and the brain says, 'I've got to fix you,'" Colton says. "I've got to make sure everything is okay so it turns on the nurturer system."

What happens is that the nurturer system is maintained for a long period of time, and it turns out to be as deadly as the warrior phase, Colton says. The way it does it is different, and it's not the same process of toxicity, she says.

"The toxicity in the nurturer phase causes nutrient deprivation. If you could imagine you pulled away the nutrients from the bacteria, you would affect that cell you pulled the nutrients away from," Colton says. "That's what we think is going on, and we have evidence to say that."

Susceptible cells are starved and the body can adapt for a while, but there's a cost if it doesn't stop and neurons die, Colton says.

Using the drug difluoromethylornithine (DFMO) before the start of symptoms in the mice, the scientists saw fewer plaques develop in their brains, and they performed better on memory tests, Colton says.

DFMO, which is taken orally, and safety toxicity is well known and being investigated in human clinical trials to treat some types of cancer, but it hasn't been tested as a potential therapy for Alzheimer's, Colton says. In the study, Colton's group administered it before the onset of symptoms; now they are investigating whether DFMO can treat features of Alzheimer's after they appear.

"What we found was that the behavior was normal," Colton says. "When you had the sick mouse, the mouse was unable to remember things. Now, they were able to go back to a controlled or normal state, which was very nice."

What the research means, Colton says, is that they are able to intervene in a specific pathway and when they did, it changed the course of the disease.

"We're never going to cure it because once you get to a certain point -- If your neurons are dead, it's going to be very difficult to replace those neurons, although people are talking about trying to put stem cells in," Colton says. "But that's way down the road in my view. The point is to try and slow the progression so we can at least enjoy aging without fear of being demented."

Colton says she remains convinced that the Alzheimer research field will find a way to combat it, and she says she believes the Duke research is a key lynchpin. The research field needs to think about new ways to approach the disease, she says.

"Is this going to going to be the end?" Colton asked. "I'm curing the disease [only] in mice. But it's an exciting possibility that perhaps this approach to thinking about how immunity is much more complex than we were suspecting. If that's the case and if it's critical to the onset, we can start thinking about ways to slow the progression. Whether this stops the onset, I can't tell you yet. We haven't done enough experiments yet. Whether this drug will stop the disease after it's been there awhile, I can't tell you that because we don't have the data. Is it going to be next year? No. Is it going to be three years from now? If we're lucky, three years from now we may be starting clinical trials with BMFO.

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