Everyone wants to build a better mousetrap, but researchers working to uncover the secrets of Alzheimer's disease have taken that a step further: They've built a better rat.
By creating genetically engineered lab animals that more closely mirror key elements of Alzheimer's in the human brain, scientists report they have created a more effective, faster approach for early testing of potential drugs to treat the disease.
These "transgenic" rats are better lab animals than are other rodents for a variety of reasons, according to study author Terrence Town, a professor in the physiology and biophysics department at the Keck School of Medicine at the University of Southern California. "You get so much more usable data from these rats."
"First, the typical rat, which is 5 million years closer to the human than the mouse is, is a better model for pathology than the mouse," Town said. Mice have typically been seen as the preferred lab animal because rats are four times more expensive to house, he noted.
Because the genetically altered rats are designed to develop specific pathologies seen in Alzheimer's, these rodents could help researchers better understand the disease process and test new therapeutics, he explained. "With mice models, you can cure them with lots of things but none have translated to humans, and we believe we're now going to close the gap with these rats."
Newly created rats give insight
Alzheimer's disease, which affects at least 5.1 million Americans, is an age-related dementia that gradually destroys a person's memory, thinking and the ability to carry out simple tasks.
Scientists have found that brain evidence of the disease includes the loss of neurons, or nerve cells; the development of abnormal levels of proteins that form what are called amyloid plaques, and the clumping of "tau proteins" inside neurons, forming what are termed "neurofibrillary tangles."
The newly created transgenic rats are the first rodents to have mutations that effectively reproduce those brain changes, according to the research.
From studying the genetically engineered rats, the researchers have confirmed the role of amyloid plaques in the development of the disease and discovered specialised glial cells (neural support cells) before the development of amyloid plaque. That suggests that activation of those cells could potentially become a new treatment target, according to Town. "We may be able to see subtle changes in humans earlier than we thought in people who are predisposed to Alzheimer's."
To create a transgenic rat, "you take a disease-causing gene from a human and you put it into an animal," Town explained. "You make a line of animals, just like you would with dogs or horses, to transmit that gene."
How the study was done
The scientists then test to be sure the rat progeny have evidence of the genetic changes and allow them to age. Rats typically have a three-year life span, so 16-month-old rats are like people in their 40s and 2-month-olds are like those in their 80s, Town noted.
The researchers tested the transgenic rats to confirm the presence of the neurofibrillary tangles in areas of the brain involved in learning and memory. They also found evidence that 30% of the rats' brain neurons in these areas died as the rats aged, with some glial cells forming themselves into shapes similar to those found in human patients.
Heather Snyder, director of medical and scientific operations for the Alzheimer's Association, said the research represents the first time critical processes and pathologies of the disease have been replicated in an animal model. But she warned that animal models are limited.
"Rats are not humans and animals do not develop Alzheimer's," Snyder noted. "This is something that is still being manipulated by the scientists - animal models are an early tool in research. So, while this type of research and this type of advance in the field is important, this is still basic science."
Town said his hope is that the transgenic rats will help researchers uncover principles applicable to other neurological diseases, such as amyotrophic lateral sclerosis - also known as ALS or Lou Gehrig's disease -- and Parkinson's disease. "As we make this model available to the research community, our hope is that it will be useful in basic research and treatment development," he said.
Learn more about Alzheimer's disease from the US National Institute of Neurological Disorders and Stroke.
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