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 mice that carry a human gene mutations that causes 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 four to five 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.