Alzheimer's disease therapeutic prevents long-term damage from TBI in pre-clinical studies

Mar 15, 2009

A class of Alzheimer's disease drugs currently studied in clinical trials appears to reduce damage caused by traumatic brain injury in animals, researchers at Georgetown University Medical Center report in an upcoming advance online publication of Nature Medicine.

They say the results suggest that this class of drugs could potentially do something no other drug has been able to do-- prevent the long-term and continuing damage that often follows a serious injury to the brain.

That is because the agents, known as gamma secretase inhibitors, are designed to prevent build-up of amyloid, a toxic peptide found in the brain. This peptide clogs the brains of Alzheimer's patients but it is has also been found in people who have died from traumatic , says the study's lead author, neuroscientist Mark Burns, PhD, an assistant professor at GUMC.

"No one knows why it occurs, but abnormal amounts of amyloid plaque have been found during an in about a third of brain injury victims, some of whom were children who would ordinarily never have had these deposits," says Burns. "Remarkably, these deposits may occur in less than one day after injury."

There is another connection between and Alzheimer's disease, he says - it is known that people who suffered a brain injury had a 400 percent increased risk of developing the disorder.

"But up until now, these were just interesting observations," Burns says. "In this study we show that the same pathways activated chronically in Alzheimer's disease are activated acutely in traumatic brain injury and that they appear to play a very important role in secondary injury."

usually produces an immediate "necrotic" death of nerve cells, but this damage is often followed by a secondary wave of injury that can last weeks, months, and even years, Burns says. This damage comes from , which is a different form of cell death, and can result in large holes in that cause lasting neurological effects. To date, there has been no way to prevent or treat this damage, he says.

In this study, the investigators sought to understand if amyloid peptide contributed to secondary injury. Amyloid peptides are produced when a long protein in the brain known as the amyloid precursor protein (APP) is cut in two by the enzyme beta secretase, and then cut into smaller pieces by a second enzyme, known as gamma secretase.

The researchers went on to test Alzheimer's disease amyloid-busting agents as a brain injury treatment. It worked. "By using a gamma secretase inhibitor, we prevented much of secondary traumatic brain injury in in our experiments," he says.

To look at the role of amyloid in brain injury, the researchers used two different approaches to blocking activation of the pathway that produces amyloid peptide. They used a group of mice that were genetically altered so that they did not produce any beta secretase, which meant they were incapable of producing amyloid.

They also treated "normal" mice with the experimental agent DAPT, one of the first gamma secretase inhibitors developed and the model upon which some Alzheimer's disease drugs now in clinical testing are based. As a result, amyloid peptide production was substantially reduced in this group.

They first showed that in a group of normal control mice, brain injury produced substantially more amyloid peptide, and that the brain region known as the hippocampus, which is also affected in Alzheimer's disease, was substantially damaged.

They then followed the groups of reduced amyloid mice after injury, and found that three weeks after initial trauma, both groups performed almost equally well on learning tests. Magnetic resonance imaging scans of the mice showed that these two groups of mice did not have "nearly the same amount of damage in the hippocampus of their brain as control mice did," Burns says.

"The experiment with the genetically altered mice shows that amyloid peptide contributes to the secondary damage seen in traumatic brain injury," he says. "If injured mice that cannot develop amyloid demonstrate reduced signs of secondary trauma, that points to amyloid peptide as a cause of this continuing damage."

The study using DAPT then proved that in mice able to produce amyloid, a gamma secretase inhibitor reduced amyloid peptide production, and significantly improved learning, Burns says. "This is an exciting finding that we hope can be readily tested in patients with traumatic brain injury," he says.

Source: Georgetown University Medical Center

Explore further: The impact of bacteria in our guts

add to favorites email to friend print save as pdf

Related Stories

Rapid changes in key Alzheimer's protein described in humans

Aug 28, 2008

For the first time, researchers have described hour-by-hour changes in the amount of amyloid beta, a protein that is believed to play a key role in Alzheimer's disease, in the human brain. A collaborative team of scientists ...

Potential Alzheimer's disease drug target identified

Mar 14, 2008

In findings with the potential to provide a therapy for Alzheimer’s disease patients where none now exist, a researcher at the University of California, San Diego and colleagues have demonstrated in mice a way to reduce ...

Anti-inflammatory drug blocks brain plaques

Jun 24, 2008

Brain destruction in Alzheimer's disease is caused by the build-up of a protein called amyloid beta in the brain, which triggers damaging inflammation and the destruction of nerve cells. Scientists had previously shown that ...

Scientists find new cause of Alzheimer's

Apr 19, 2006

Belgium researchers say they are the first to demonstrate the quantity of amyloid protein in brain cells is a major factor of Alzheimer's disease.

Recommended for you

The impact of bacteria in our guts

Aug 22, 2014

The word metabolism gets tossed around a lot, but it means much more than whether you can go back to the buffet for seconds without worrying about your waistline. In fact, metabolism is the set of biochemical ...

Stem cell therapies hold promise, but obstacles remain

Aug 22, 2014

(Medical Xpress)—In an article appearing online today in the journal Science, a group of researchers, including University of Rochester neurologist Steve Goldman, M.D., Ph.D., review the potential and ch ...

New hope in fight against muscular dystrophy

Aug 22, 2014

Research at Stockholm's KTH Royal Institute of Technology offers hope to those who suffer from Duchenne muscular dystrophy, an incurable, debilitating disease that cuts young lives short.

Biologists reprogram skin cells to mimic rare disease

Aug 21, 2014

Johns Hopkins stem cell biologists have found a way to reprogram a patient's skin cells into cells that mimic and display many biological features of a rare genetic disorder called familial dysautonomia. ...

User comments : 0