A normally protective enzyme in the powerhouse of brain cells can get knocked out and cause the sort of dysfunction that could lead to Alzheimer's disease, the dean of the Medical College of Georgia's School of Medicine said.
In addition to his job in Augusta, David M. Stern is working on research with former colleagues at Columbia University in New York, and their latest effort on the roots of Alzheimer's disease appears today in the journal Science.
The Columbia researchers had been looking at interactions with a form of protein that has long been implicated in damage to neurons in Alzheimer's and came up with the enzyme, called amyloid beta alcohol dehydrogenase, or ABAD.
When mice are bred to produce a lot of this enzyme, it seems to have good effects, Dr. Stern said.
When given a drug that normally produces symptoms in mice similar to those of Parkinson's disease, "We could prevent that (the symptoms) in mice that overexpressed ABAD," he said.
More confirmation came when looking at a rare birth defect in people who lacked this enzyme. In the five or six cases known worldwide, those patients suffered developmental problems and neurodegeneration, Dr. Stern said.
"This told us that if this enzyme doesn't work, it can potentially have bad effects for neurons," he said.
The enzyme is important for the mitochondria, which provide energy for the cell and without which cells can't survive.
With the failure of a recent experimental vaccine and other drugs, researchers are turning away from the buildup of amyloid beta plaques outside the cell and are focusing on what is happening inside, particularly to the mitochondria, said Patricia Trimmer, a researcher at the Center for the Study of Neurodegenerative Diseases at the University of Virginia.
"The idea that amyloid buildup outside the cells is toxic is sort of losing favor in the community because it doesn't make a lot of sense," Dr. Trimmer said. "It makes more sense that the amyloid is released into the cell, that there are fragments that get released into the cell and that those fragments are the ones causing the damage. They would then be able to reach the mitochondria and get inside and interact with it."
The Columbia group was able to show that not only can amyloid beta get into mitochondria, which was previously unproved, it also can knock out the enzyme by binding on to it.
"It's really turning a protective mechanism on itself," Dr. Stern said.
Mice that were bred to produce more of the enzyme and the amyloid protein showed "Alzheimer's-like" symptoms, Dr. Stern said.
The team also created a protein piece that looked like the part of the enzyme that attaches to the amyloid protein.
This "decoy" peptide blocked the amyloid beta from knocking out the enzyme.
"The (decoy) peptide actually intercepts the interaction," Dr. Stern said. "Now, is the peptide an ideal drug? Probably not, but it's a good way to test the concept."
The idea might be to prevent the initial damage from the amyloid protein that could spiral into Alzheimer's, when recovery might still be possible, he said.
"Maybe if we can prevent those more acute problems, then the body's mechanisms can (break it down) and make the stuff go away," Dr. Stern said.
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