Mouse Model Offers Effective Tool in Screening for
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
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
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
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
"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
"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
This work was supported by grants from the National
Institute on Aging, of the National Institutes of Health.
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