Scientists Pinpoint Key Player in Characteristic Brain Changes

By Liza Jane Maltin
　　WebMD Medical News

Reviewed by Dr. Aman Shah

Despite decades of research, a successful cure for Alzheimer's disease continues to elude us. Now, two separate research teams have taken what may be a huge leap forward. They have identified the enzyme that causes amyloid plaques -- clumps of protein believed to destroy brain cells and bring on disease symptoms. And identifying what causes the plaques is the first step in preventing them. "This is huge news for drug development," the researchers tell WebMD.

In the first study, Philip C. Wong, PhD, and colleagues at Johns Hopkins University School of Medicine created mice without the gene for BACE1 -- the enzyme in question. They then took brain cells from those mice, and showed that they did not produce any of the protein that forms amyloid plaques.

"You have to be careful when you find drugs to inhibit enzymes, to know if the enzyme has effects on other pathways that are important to the animal's development," says Wong, an associate professor in the department of pathology. Even though his mice lacked the BACE1 enzyme, they were perfectly healthy. This means that any drug used to inhibit BACE1 and prevent amyloid plaque formation in humans would be unlikely to cause serious side effects, he tells WebMD.

Wong's team is now looking at whether removing BACE1 from mice at risk for Alzheimer's will reduce or prevent plaque formation, and keep them from developing the disease.

Research scientist Robert Vassar, PhD, and colleagues at the biotechnology firm Amgen have already taken things that step further. While Wong's team looked at nerve cells in a test tube, Vassar's team looked at nerve cells in the brains of living mice at risk for Alzheimer's disease.

"Both Wong's team and ours have both completely eliminated the BACE1 protein and got the same results in that we see mice that are totally normal but make no [plaque-forming] protein in the brain," says Vassar.

These animals are only 8 months old, and it normally takes about a year for plaques to develop. "The next step is to let them age and see if they ever develop amyloid plaques," says Vassar. "We predict that they won't."

"These were the best possible results," says Vassar. "Normal mice and no [plaque-forming] protein in the brain. It means that inhibiting BACE1 in humans will probably be free from bad side effects, and that gives us confidence going into clinical trials. For drug companies, this is huge news."

Fiona C. Crawford, PhD, agrees. "This is very exciting," she tells WebMD in an interview seeking an objective assessment of the research. "It means that BACE1 inhibition is likely to be safe." Crawford is associate director of the Roskamp Institute at the University of South Florida College of Medicine in Tampa.

The findings "give a green light to further intensive explorations of the BACE1 system," says David Olson, MD, a staff neurologist at Georgia Regional Hospital in Atlanta, and medical advisor to WebMD. "Turning off this enzyme with a drug may reduce the amount of [plaque-protein] formation and ultimately decrease the clinical manifestations of Alzheimer's disease."

The research appears in the March issue of the journal Nature Neuroscience.

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