Mouse Model Offers Effective Tool in Screening for Alzheimer's Medications

(Philadelphia, PA) - Researchers at the University of Pennsylvania School of Medicine have found direct evidence that mild repetitive head injuries can lead to Alzheimer's disease. Their evidence suggests that brain trauma accelerates Alzheimer's by increasing free radical damage and the formation of plaque-like deposits of Amyloid beta (Ab) proteins. Perhaps just as importantly, the special breed of mice developed for the study could serve as a model in screening drugs to treat Alzheimer's and traumatic brain injuries. Their findings are published in the January 15 issue of The Journal of Neuroscience.

"This is the first experimental evidence linking head injuries to Alzheimer's disease by showing how repetitive concussions can speed up the progress of the disease," said Kunihiro Uryu, PhD, a senior research investigator at Penn's Center for Neurodegenerative Disease Research (CNDR). "It also shows the tremendous utility of the transgenic mice and the trauma model we have developed for Alzheimer's research."

In recent years, researchers have made remarkable progress in uncovering the genetic basis of inherited Alzheimer's disease. They do not, however, know much about the causes of the sporadic, or non-inherited, forms of the disease despite the fact that almost 90% of all Alzheimer's cases can be termed sporadic. While there are a few documented genetic risk factors that predisposes a person to Alzheimer's, one very robust environmental factor, head trauma, has been identified. Although recurrent head trauma is thought to cause Punch Drunk Syndrome (dementia pugilistica) in boxers, researchers had been unable to prove a mechanistic link between head injury and Alzheimer's.

Until now, however, researchers have lacked a good animal model for studying the development of Alzheimer's disease. The transgenic mice used in the CNDR contain the human gene that produces the Ab protein. With the aid of techniques developed at the Penn Head Injury Center, Uryu and his colleagues were able to study how just mild repetitive head injuries could influence the progress of Alzheimer's disease.

Even without head trauma, these mice would eventually develop Ab plaques later in life. With the trauma, they produce symptoms of Alzheimer's disease at a remarkably increased rate.

"Here, we can clearly see a direct cause and effect relationship between repetitive concussions and Alzheimer's," said John Q. Trojanowski, MD, PhD, co-director of the CNDR and professor in the Department of Pathology and Laboratory Medicine. "Using the head trauma model in these mice represents a step forward in our ability to understand the basic molecular mechanisms behind Alzheimer's disease. More importantly, we believe this model system can be used to screen for new medications in the search for a cure."
While there are a number of medications that treat the symptoms of Alzheimer's, there are no medications, as yet, that address the root of the disease.

Over the course of the study, mice were sedated and given mild repetitive concussions. In the ensuing weeks, Uryu and his colleagues monitored their behavior and brain pathology. In addition to looking for deposits of Ab, they also monitored amounts of a molecule called isoprostane. Last year, Penn researchers discovered that urine isoprostane levels serve as an indicator of the sort of free radical damage found in Alzheimer's disease.

"Two days after the injuries, and again at nine and sixteen weeks, we measured amyloid deposits and levels of isoprostanes and amyloid beta proteins," said Uryu, "At each point, we saw a dramatic increase of indicators for Alzheimer's disease in the mice that received repetitive head traumas.

According to their findings, repetitive - but not single - mild traumatic brain injuries increased Ab deposition as well as levels of Ab and isoprostanes in the transgenic mice. The repetitive injuries induced cognitive impairments in the mice, but did not interfere with their motor functions and dexterity.

Upward of four million Americans suffer from Alzheimer's disease, a statistic that is likely to rise along with the aging population. Alzheimer's develops slowly, beginning with frequent memory problems and resulting in severe brain damage. Within the brain, amyloid plaques and fibrous tangles of nervous tissue tangles choke off and eventually destroy brain cells. Eventually, sufferers require fulltime medical care.

"Alzheimer's disease has a very real and understandable molecular basis and it will be curable," said Trojanowski. "Developing a working animal model of how head trauma augments Alzheimer pathology, as we have in our studies here, is just one more step in reaching the inevitable treatment."

This work was supported by grants from the National Institute on Aging, of the National Institutes of Health.

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