Alzheimer's may hijack chemical mechanism

By Julie Steenhuysen

CHICAGO, 19 feb 2009– U.S. scientists proposed a new theory on Wednesday of how Alzheimer's disease kills brain cells they said opens new avenues of research into treatments for the fatal, brain-wasting disease.

They believe a chemical mechanism that naturally prunes away unwanted brain cells during early brain development somehow gets hijacked in Alzheimer's disease.

"The key player we're focusing on is a protein called APP," said Marc Tessier-Lavigne, executive vice president of research drug discovery at the U.S. biotechnology company Genentech Inc, whose study appears in the journal Nature.

Tessier-Lavigne said amyloid precursor protein, or APP -- a key building block in brain plaques found in Alzheimer's disease -- is the driving force behind this process.

"We know that APP is a bad actor in Alzheimer's, but it has been unclear how it participates," he said in a telephone interview.

Tessier-Lavigne thinks that somehow this self-destruction mechanism gets switched on in Alzheimer's disease and starts killing healthy brain cells.

The finding provides new clues about potential treatments for Alzheimer's, a disease that gets worse over time and is marked by memory loss, confusion and eventually the inability to care for oneself.

The researchers made the Alzheimer's connection by accident while studying a process of nerve cell self-destruction that occurs as a part of normal embryonic development.

When the brain and spinal cord are being formed, excess nerve cells are generated that have to be removed to refine the pattern of nerve cell connections.

They discovered a biochemical mechanism that activates when nerve cells are pruned back. "A key component of this self-destruction program was none other than APP, this bad actor in Alzheimer's disease," Tessier-Lavigne said.

"We were stunned," he added.

"This immediately raised the possibility that in Alzheimer's disease, where we know APP is involved, it is involved by virtue of this mechanism."

In Alzheimer's disease, enzymes snip APP into beta amyloid pieces, which form the basis of beta amyloid plaques that are thought to be toxic.

Many companies are working on drugs to remove beta amyloid from the brain, but so far have had little success in altering the course of the disease.

Tessier-Lavigne's theory suggests targeting APP and other components of this mechanism may help. In tests on human embryonic cells, the team showed it was able to interfere with the mechanism and block the degeneration of nerve cells.

The researchers now plan to see if they can disrupt this mechanism in adult brain cells.

"The key question is, if we interfere with it, can we halt the progression of the disease?" Tessier-Lavigne said.

There is no cure for Alzheimer's, and current drugs merely delay symptoms. It affects 5.2 million people in the United States and 26 million globally, according to the Alzheimer's Association.