A Prenatal Link to Alzheimer's?

A Prenatal Link to Alzheimer's? By Ron Winslow
Researchers Propose Process in Fetal Development Is Reactivated Later in Life
WSJ, Feb 19, 2009

New research at Genentech Inc. is challenging conventional thinking about Alzheimer's disease, providing a provocative theory about its cause and suggesting potential new targets for therapies to treat it.

The researchers propose that a normal process in which excess nerve cells and nerve fibers are pruned from the brain during prenatal development is somehow reactivated in the adult brain and "hijacked" to cause the death of such cells in Alzheimer's patients.

The dominant view of Alzheimer's disease today is that it is caused by deposits called beta amyloid that accumulate in the brain because of bad luck or other unknown reasons, degrading and destroying nerve cells and robbing victims of their memory.

The new findings offer evidence that "Alzheimer's is not just bad luck, but rather it is the activation of a pathway that is there for development purposes," says Marc Tessier-Lavigne, executive vice president, research drug discovery, at Genentech. "It suggests a different way of looking at Alzheimer's disease."

[photos in original article]

The report, being published Thursday in the journal Nature, is based on laboratory and mouse experiments, and further study is needed to validate the hypothesis.
Genentech, a South San Francisco, Calif., biotech company, says it has identified potential drug candidates based on the findings, but even if they prove promising, it would take several years for any potential treatment to be developed.

Beta amyloid, a fragment of a larger molecule called amyloid precursor protein, or APP, has long been the dominant focus of Alzheimer's research. Many drug companies have compounds in development that are intended to block or clear the buildup of beta amyloid plaques in the brain. But the track record for developing effective drugs has been unimpressive so far. Moreover, some people accumulate beta amyloid in the brain without any apparent effect on memory, adding to confusion about its role in Alzheimer's.

During human development, the prenatal brain makes about twice the number of nerve cells it needs, Dr. Tessier-Lavigne explained. Those neurons, in turn, each make hundreds of nerve fibers that seek to make connections with other cells. The cells and nerve fibers that succeed in making connections survive -- while those that don't naturally trigger a self-destruction mechanism called apoptosis that clears out the unneeded cells.

"We make too many, and then we prune back," Dr. Tessier-Lavigne said. "The system gets sculpted so you have the right set of connections."

What he and his colleagues, including scientists from the Salk Institute, La Jolla, Calif., found is that the amyloid precursor protein linked to Alzheimer's also plays a critical role in triggering the prenatal pruning process. But the beta amyloid that appears to kill nerve cells in Alzheimer's patients isn't involved in the developing embryo. Instead, the pruning is sparked by another fragment of APP called N-APP, causing a cascade of events that results in the death of excess nerve cells and nerve fibers.

"This suggests that APP may go through a novel pathway rather than beta amyloid to cause Alzheimer's disease," says Paul Greengard, a scientist at Rockefeller University, New York, and a Nobel laureate who wasn't involved in the research. He called the paper "an important step" in understanding the pathology of Alzheimer's -- something that is necessary to develop better drugs.

Don Nicholson, a Merck & Co. vice president and author of a commentary that accompanies the Tessier-Lavigne study in Nature, said the paper doesn't rule out a role for beta amyloid. He added that given the intense focus on the role of beta amyloid in the disease, the finding that another part of the precursor protein may be important in Alzheimer's is "unexpected biology."

Exactly what triggers the reappearance in the adult brain of a process fundamental to its early prenatal development isn't clear and is the subject of continuing research, Dr. Tessier-Lavigne said. Meantime, there are several steps in the cascade of events that lead to the death of the developing neurons and nerve fibers. If the process reflects the unwanted death of such cells in Alzheimer's, it presents several places where a drug could block or affect the process to possibly prevent the damage.

"We've identified a mechanism of nerve-cell death and degeneration involving amyloid precursor protein in the embryo," he said. "What Alzheimer's is doing is hijacking not only the molecule but the whole mechanism of degeneration."

Meantime, a second paper published last month by a team including researchers at Buck Institute for Age Research, Novato, Calif., reported that a protein called netrin-1 appears to regulate production of beta amyloid. The finding, which appeared in the journal Cell Death and Differentiation, is behind the authors' belief that Alzheimer's is the result of normal processes going awry.

Together the papers add to intriguing evidence that beta amyloid is perhaps only part of the Alzheimer's story. "What we're seeing is a completely different view of the disease," said Dale Bredesen, a Buck Institute researcher and co-author of the paper. The brain has to make connections and break connections all the time. Alzheimer's, he suggests, is the result when that process is out of balance.