Data suggests potential target for Alzheimer's disease treatment

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May 25 2004

Researchers from Weill Cornell Medical College and Columbia University College of Physicians & Surgeons have discovered at least one way in which beta-amyloid, the protein that forms stubborn plaques in the brains of Alzheimer's disease patients, can kill nerve cells.

Nerve cell death is a hallmark of the memory-robbing disorder, and is thought to be the cause of personality changes and other neurological changes that occur with the disease.

According to a report in the April 16 issue of the journal Science, beta-amyloid, a protein long known to accumulate in plaques in the brains of Alzheimer's patients, binds to a protein known as ABAD (beta amyloid-binding alcohol dehydrogenase).

Finding a way to inhibit this interaction may help prevent nerve cell death, and possibly help prevent the symptoms of Alzheimer's disease, according to the research team led by Dr. Hao Wu, Professor of Biochemistry at Weill Cornell Medical College and Weill Cornell Graduate School of Medical Sciences in New York; Dr. Shirley ShiDu Yan, Associate Professor of Clinical Pathology at Columbia University College of Physicians & Surgeons in New York; and Dr. Joyce Lustbader, Senior Research Scientist in Obstetrics and Gynecology at Columbia P & S.

This interaction between beta-amyloid and ABAD takes place in the mitochondria, which are energy-producing powerhouses inside cells. The study, although preliminary, suggests that this interaction causes the mitochondria to malfunction, triggering apoptosis, or a programmed cell death, that leads to the destruction of nerve cells, the researchers said.

In the study, the researchers compared brain tissue from Alzheimer's disease patients to brain tissue from patients the same age who had died of other causes. They found that ABAD and beta-amyloid are bound together tightly in brain tissue from Alzheimer's disease patients, but not in the brain tissue of people without the disease. In additional experiments, they determined the three-dimensional crystal structure of the two components — ABAD and beta-amyloid — as they bind together.

"The crystal complex is the first demonstration that beta-amyloid peptide binds to a protein called ABAD and accumulates inside the mitochondria in brain cells," said Dr. Lustbader.

"We used the crystal structure of the ABAD and beta-amyloid complex to design an inhibitor — a short protein known as a peptide — that would prevent the two from binding together," said Dr. Wu.

In a series of experiments in laboratory-grown nerve cells, the researchers demonstrated that the peptide inhibitor could prevent nerve cell death.

"You can take normal human nerve cells and treat them in the laboratory with beta-amyloid and the cells will die, essentially. This also happens with cells from transgenic mice that have Alzheimer's disease-like symptoms," said Dr. Wu. "But if you pre-treat nerve cells with this inhibitor peptide, they won't die. It appears to protect cells in the laboratory," she said.

Additional research in nerve cells suggested that beta-amyloid may change the shape of ABAD, which disrupts its function and leads to the generation of reactive oxygen species, the researchers said. Reactive oxygen species are "free radicals," or DNA-damaging reagents that are byproducts of cellular metabolism. Excessive generation of reactive oxygen species can cause nerve cells to malfunction.

Many researchers believe that Alzheimer's occurs when beta-amyloid clusters in, and ultimately kills, brain cells by causing the production of destructive free radicals in the mitochondria. In experiments in special transgenic mice that produce both ABAD and beta-amyloid, the researchers showed the animals had higher levels of free radicals and more problems with learning and memory than normal mice. "This could be what happens in the early stage of Alzheimer's disease when you don't have a lot of deposits but you do have some beta-amyloid," said the researchers. "This enzyme-protein complex makes the cells more vulnerable to dying."

The next step is to test the peptide directly in transgenic mice with Alzheimer's disease-like symptoms, the researchers said.

"Our findings suggest that one way to treat Alzheimer's would be to develop a drug that prevents the beta-amyloid peptides from binding with ABAD, which might prevent the cascade of damage that Alzheimer's typically leads to," Dr. Yan said. However, more study is needed. Although the peptide inhibited ABAD-beta amyloid interaction in laboratory-grown cells, much more research is necessary to see if it works in the more complex environment inside the brain of a living animal.

The study was funded in part by the National Institutes of Health and the Speaker's Fund for Biomedical Research.