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5:15 pm
Tue April 9, 2013

Genetically Modified Rat Is Promising Model For Alzheimer's

Originally published on Tue April 9, 2013 7:34 pm

A rat with some human genes could provide a better way to test Alzheimer's drugs.

The genetically modified rat is the first rodent model to exhibit the full range of brain changes found in Alzheimer's, researchers report in The Journal of Neuroscience.

"It's a big step forward" for drug development, says Roderick Corriveau, a program director at the National Institute of Neurological Disorders and Stroke, or NINDS, which helped fund the work. "The closer the model is to the human condition in representing the disease, the more likely the drug will behave and cure the way it would in humans."

In recent years, drug companies have developed several Alzheimer's drugs that seemed to work in animals, but did not help people with the disease. A lack of good animal models for Alzheimer's may be one reason for those failures, researchers say.

For the past couple of decades, Alzheimer's researchers have relied primarily on mice that carry human gene mutations that cause people to get the disease in their 40s or 50s. Like people, these mice develop so-called amyloid plaques in their brains.

But that's where the similarity ends. In people with Alzheimer's, after plaques appear, huge numbers of brain cells die. That's never happened in mice, despite lots of genetic tinkering, Corriveau says.

So researchers began to consider a different rodent model: the rat. "Rats are 4 [million] to 5 million years closer evolutionarily to humans," Corriveau says, which means their brains are more like ours.

But early efforts to insert Alzheimer's gene mutations into rats didn't work any better than with mice, he says. Then a group of scientists began studying a line of rats that are known to get some of the same health problems people do as they get older.

"We thought that they would be sort of on the cusp of normal aging," says Terrence Town, a professor of physiology and biophysics at the University of Southern California. "And then if we added into that mix these mutant human genes that cause Alzheimer's, we might have a much better and much more full model of the human syndrome."

Once they inserted the mutant genes, the rats began to develop plaques in their brains, just like the mice had, Town says. But unlike the mice, he says, these rats also developed so-called tangles in their brain cells, another hallmark of Alzheimer's.

"The big shocker came when we started counting numbers of neurons in their brains," Town says. "It turns out that they lose up to about 30 or 35 percent of the neurons in brain regions that are classically associated with Alzheimer's disease."

The rats also began to lose their ability to do mental tasks, like navigate a maze. And as the animals get older, Town says, "they perform even worse, much as you would see in a human being that would have these mutations."

Town's lab has already begun testing some potential Alzheimer's drugs on the new rats. And Town says he's already getting calls from other scientists who want to try the new rats in their labs.

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Transcript

AUDIE CORNISH, HOST:

The field of Alzheimer's research is about to get a boost from a very special rat. This week in the Journal of Neuroscience, there's a report about the first rodent to develop the full range of brain problems that affect people with Alzheimer's. Scientists hope the rat will lead to a better understanding of how the disease damages the brain and which drugs might halt its progress. NPR's Jon Hamilton explains.

JON HAMILTON, BYLINE: For about two decades now, researchers have been studying Alzheimer's disease using mice - not just any mice. These rodents carry the same human gene mutations that cause people to get the disease in their 40s and 50s. And Rod Corriveau of the National Institute of Neurological Disorders and Stroke says, in one important way, the brains of these mice do resemble those of Alzheimer's patients.

DR. ROD CORRIVEAU: The mice developed what's called plaques, amyloid plaques that can contain the protein fragment that's thought to cause Alzheimer's disease.

HAMILTON: But that's where the similarity ends. In people with Alzheimer's, after plaques appear, huge numbers of brain cells die. Corriveau says that's never happened in mice despite lots of genetic tinkering.

CORRIVEAU: And while we learn many things and came up with different varieties of Alzheimer's models, no matter what combinations they tried, there's still been this huge gap. There just haven't been a significant number of neurons dying.

HAMILTON: So Corriveau says researchers began to consider a different rodent model: the rat.

CORRIVEAU: The rats are 4 to 5 million years closer evolutionarily to humans, so let's try rats and maybe we'll get that feature of neuronal cell death.

HAMILTON: Researchers did try. They put various combinations of human Alzheimer's genes in rats. But it didn't work. Then a group of scientists began studying one particular family line of rats. Terrence Town, at the University of Southern California, says when these rats got older, they got some of the same health problems people do.

DR. TERRENCE TOWN: That's actually why we chose this line because we thought that they would be a sort of on the cusp of normal aging. And then if we added into that mix these mutant human genes that cause Alzheimer's, we might have a much better and much more full model of the human syndrome.

HAMILTON: Town says once they inserted the mutant genes, the rats began to develop plaques in their brains, just like the mice had. But he says, unlike the mice, the rats also developed so-called tangles in their brain cells, another hallmark of Alzheimer's.

TOWN: The big shocker came when we started counting numbers of neurons in their brains. And it turns out that they lose up to about 30 or 35 percent of the neurons in brain regions that are classically associated with human Alzheimer's disease.

HAMILTON: Something that had never happened in mice. And there was one more thing. Town says as the rats lost brain cells, they also began to lose their ability to do things like navigate a maze.

TOWN: They perform much more poorly on a variety of these tests of learning and memory. And in addition, as the animals age, they perform even worse, much as you would see in a human being that would have these mutations.

HAMILTON: Rod Corriveau, from the NIH, says the new rat model should give researchers a better way to study how amyloid plaques and tangles kill off brain cells. And, he says, it should allow something that's of more practical use to people with Alzheimer's.

CORRIVEAU: What it allows is the best possible opportunity to discover drugs that will work in humans. The closer the model is to the human condition in representing the disease, the more likely the drug will behave and cure the way it would in humans.

HAMILTON: Terrence Town says he's already begun testing drugs on the new rats. And he says lots of other scientists have asked to try these rats in their labs. Jon Hamilton, NPR News. Transcript provided by NPR, Copyright NPR.