New York Times Syndicate - January 19, 2006

New findings on the origins of Alzheimer's disease, if confirmed,

could turn prevailing theories on their heads, researchers contend.

Scientists reporting in the Jan. 18 issue of The Journal of

Neuroscience say the neurodegenerative disease may be triggered when

adult nerve cells, or neurons, try to divide.

The work was done in mice and needs to be confirmed in subsequent

studies, the researchers stressed. However, the results may provide

additional insight into the early cellular events that lead to

Alzheimer's in humans.

"It really is going against the central grain of what we know, and it

actually may lead to something more promising," says Danilo Tagle,

program director in neurogenetics at the U.S. National Institute of

Neurological Disorders and Stroke, which sponsored the study.

Other experts are playing down the novelty of the findings.

"It's another piece of the puzzle falling into place, but I would not

say it debunks other theories," says Maria Carrillo, director of

medical and scientific affairs at the Alzheimer's Association.

"This particular piece gives more information about what cell

division is doing before you get to the disease state."

The prevailing theory of Alzheimer's is that it is caused by a

buildup of amyloid plaques in the brain that cause neurons to divide

and die. Cells divide through a process called the "cell cycle." In

most cases, neurons usually do not participate in this process, however.

"In regular cells, like in bone and blood, the cells divide.

But brain cells do not normally divide," Tagle explains. "The great

majority will not divide. The neurons you're born with are pretty

much what you have at end of life."

When adult nerve cells do enter this cycle, however, they will die

rather than complete the division. "Cells become stuck in the process

of cell division," Tagle explains.

The authors of this study, based at Case Western Reserve University's

Alzheimer's Disease Center in Cleveland, used mouse models to see if

other processes might be at play. To that end, they compared brains

cells of three different mouse models of Alzheimer's with brain cells

sourced from normal mice.

Alzheimer's mice showed evidence of cell cycling six months before

any amyloid plaques showed up, the researchers noted. These neurons

also had extra chromosomes, another sign that they had begun to

divide. Most of this activity was seen in the cortex and hippocampus

regions of the brain, which are most implicated in Alzheimer's.

This would seem to indicate that the formation of amyloid plaques in

the brains of Alzheimer's patients is more a byproduct or adjunct of

the disease rather than the initiating mechanism.

"The finding would indicate that there are earlier events that are

happening that precede the plaque buildup," Tagle says. "The authors

have demonstrated in animal models that these changes are happening

as early as six months before the first signs of plaque accumulation.

This seems to be a separate cellular process unlinked to the plaque

process.

"This overturns the central dogma of Alzheimer's disease," Tagle

continues. "It opens up the possibility that this is the event that's

actually triggering the cells to die. The plaques then would be like

red herrings that are a secondary process, and the abnormal cellular

process is primary."

The next step will be to see if disrupting the cycle would cause

neurons to survive. To that end, the study authors are conducting

experiments to see if the painkiller ibuprofen can stop the cell

cycle process, and thereby neurodegeneration. Ibuprofen, an anti-

inflammatory drug, has been shown to reduce the production of amyloid-

beta plaques.

"That would actually lead to less cell death in Alzheimer's, so that

would certainly be something that would lessen the impact of the

disease," Tagle says.

"This clearly supports the idea that there is more to the story,"

Carrillo adds. "Where exactly those pieces fit, we don't know yet."

(The HealthDay Web site is at http://www.HealthDay.com.)