A protein long suspected as the culprit behind the brain disorder might actually release not just one, but two components that can cause nerve cells to self-destruct. In theory, the breakdown of the protein, called APP for short, could unleash a double whammy of harmful effects on nerve cells.

Much of the drug research in the field now focuses on the first component of APP discovered to have a strong link to Alzheimer's disease. That component, the amyloid beta peptide, collects in abnormal plaques in the brain that are a diagnostic sign of the ailment.

But a second molecule split off from APP, the N fragment or N-APP, was found to trigger a chain of events that also destroys neurons, according to a paper by researchers at Genentech of South San Francisco and the Salk Institute of La Jolla. The study was published Wednesday by the prestigious scientific journal Nature.

"Now, instead of having one dog in the race, there are two, " said Paul Greengard, a professor at the Rockefeller University in New York who won the Nobel Prize in physiology or medicine in 2000 for his work on nerve cell communication. "It's a very exciting paper. It's going to have a major impact on research in the Alzheimer's field."

Marc Tessier-Lavigne, executive vice president of research drug discovery at Genentech and a co-author of the Nature paper, said the research team has yet to prove that the N fragment is a causative factor of Alzheimer's disease in aging adults. Its role in the nerve-death pathway was discovered in mouse embryos, where it helps "prune" disused nerves as part of the normal process of brain development. But the same molecules in the neurodegenerative pathway in embryos are present in adult brains, Tessier-Lavigne said. And, he said, it's not unusual for diseases to "hijack" normal body mechanisms.

Avenue of research

Experts agree that the new discovery opens up a productive avenue of research in Alzheimer's disease. Donald Nicholson, an expert in cell death pathways and vice president of basic research at Merck, said effective therapies might need to block both the neurotoxic effect of the amyloid beta peptide and the destruction wreaked by the N fragment. Merck, Genentech and other companies are currently working on experimental drugs to thwart the amyloid beta peptide in Alzheimer's disease, which causes dementia and afflicts as many as 4.5 million Americans.

"The question is, how much of the neurodegeneration is triggered by the amyloid beta peptide and how much by N-APP?" Nicholson said.

Tessier-Lavigne said his team is already studying that question, but so far researchers have only theories. "One could be involved in the initiation of the disease, and one could be involved in its progression," he said. "One could augment the effects of the other."

While probing the relative roles of the two components of APP, Genentech has started to test experimental drugs that could interrupt the cascade of destruction launched by the N fragment. The biotechnology company, a leader in cancer drug innovation, has been branching out into new fields including neurobiological disease.

Postdoctoral project

The work published in Nature began as a research project by then-Genentech postdoctoral fellow Anatoly Nikolaev under a company policy that allows postdocs to explore fundamental biological mechanisms, even if their relationship to drug discovery is not immediately apparent, said Tessier-Lavigne. The research team studied the way the embryonic brain is "remodeled" after nerve cells are born. The nerves initially produce a lush outgrowth of fibers or axons that are capable of making connections with other neurons.

Later, the nerves are "pruned" to eliminate those that have made no useful ties. The team found that a molecule called DR6 or death receptor 6 could induce unwanted nerves to commit suicide. But the scientists were exhilarated when they found that the factor that activated DR6 was the N fragment of APP, the long-recognized "bad actor" behind Alzheimer's disease. Nikolaev has since been hired as a Genentech scientist.

The N-APP molecule used to be seen as a bit of unimportant debris released by the splitting of APP, said Nicholson. Scientists gave all their attention to the amyloid beta peptide due to its known neurotoxic effects, he said.

By identifying N-APP as a key factor in the brain's "remodeling," the Nature paper makes an important contribution to the understanding of early nervous system development, Nicholson said. In addition, elements of the cell death pathway N-APP triggers are linked to Huntington's disease, and possibly other neurodegenerative disorders.

"It might also be part of the jigsaw puzzle that is Alzheimer's disease," Nicholson said.

E-mail Bernadette Tansey at btansey@sfchronicle.com.

This article appeared on page A - 1 of the San Francisco Chronicle