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Missing Enzyme Tied to Alzheimer's

May be responsible for protein tangles in brain, study finds

(HealthDay is the new name for HealthScoutNews.)

THURSDAY, July 31, 2003 (HealthDayNews) -- A missing enzyme may be responsible for the "tangles" of proteins that form in the brains of people with Alzheimer's disease.

That suggests the enzyme, called Pin1, may play a protective role in the aging brain.

The discovery is reported in the July 31 issue of Nature.

Alzheimer's disease, a neurodegenerative condition that affects people as they age, is marked by a progressive loss of mental function. The brains of people with Alzheimer's have been shown to possess two distinctive characteristics: "tangles" in the brain's neurons and "plaques" made up of amyloid protein.

More research to date has focused on plaques rather than on tangles, says Bill Thies, vice president of medical and scientific affairs for the Alzheimer's Association.

"This is an interesting study, and in an area where I think people at the moment are paying a little less attention because so many of the amyloid-limiting strategies are getting closer to clinical trials and will be tested first," he says. "That shouldn't keep us from continuing this kind of work because it might turn out the amyloid hypothesis isn't right or that it's partially right. This doesn't set the world of Alzheimer's on its head, but it's part of ongoing progress in the field."

The brain tangles are made up of a protein called tau, which is also present in normal cells. "In healthy cells, its function is both to assemble and maintain the cell's scaffolding apparatus that stretches from one end of a nerve cell to another and ferries nutrients and structural components," explains study author Dr. Kun Ping Lu, an associate professor of medicine at Harvard Medical School.

Thies likens the system to a set of railroad tracks that transport essential materials between the nerve cell body and the extremities of the cell. The tau protein could be seen as the railroad ties that hold the system together.

In people with Alzheimer's disease, the tau protein acquires too many extra phosphate groups, changes shape and collects into these tangles, which destroy neurons in that area of the brain.

Not only have tangles been overlooked compared with plaques, but the scientists have tended to focus on the overexpression of genes rather than the underexpression. "We went in a completely different direction: how to protect the neuron from undergoing age-dependent degeneration," Lu says. "We identified Pin1, an enzyme which changes the shape of the protein in the neuron. This suggests that Pin1 may play an important role in protecting neurons."

To test the hypothesis, Lu and his colleagues performed two experiments.

First they compared Pin1 levels in different regions of brains of both healthy people and people who had died of Alzheimer's. "There was a striking difference in levels of the enzyme in different regions of brains," Lu reports. "The areas of the brain that had been destroyed by Alzheimer's (such as certain parts of the hippocampus) tended to have very low levels of Pin1. That suggests Pin1 may help protect against neurodegeneration."

Next, the researchers looked at mice that had had the gene for Pin1 removed. All of these mice went on to develop age-related neurodegeneration changes, including tangle formation and loss of neurons that occur in patients with age-dependent Alzheimer's disease. This is the first time that removing a gene had resulted in the development of these structures. Also, Lu points out, it's the first study to show Pin1 is important in preventing age-dependent neurodegeneration.

As is so often the case, the discovery won't translate into practical help anytime soon but, Thies says, "it might give us a window on a mechanism that could be useful."

The next step might to find out if people with Alzheimer's had a genetic variation that caused them to produce less of Pin1, Thies says.

Finding out why Pin1 expression is low in certain vulnerable individuals may give researchers ideas for new therapies, Lu agrees.

It would be easier if more of the enzyme were needed. "The enzyme is protective," Thies points out. "You'd have to find some way to keep it from being turned off and that's harder to do. Probably there's a good deal of development work before this becomes anything that has a huge impact on people."

As a footnote to this study, Lu's lab has also discovered Pin1 is overexpressed in many human cancers and plays an important role in the development of cancer. "It would appear that certain cancers share common genetic elements with Alzheimer's disease, suggesting that Pin1 may prove to be the missing link between these two seemingly distinct areas of disease, both of which grow much more common with age," Lu says.

More information

For more information, visit the Alzheimers Association or the National Institute of Neurological Disorders and Stroke.

SOURCES: Kun Ping Lu, M.D., Ph.D., associate professor, medicine, Harvard Medical School, Boston; Bill Thies, Ph.D., vice president, medical and scientific affairs, Alzheimer's Association, Chicago; July 31, 2003, Nature
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