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Brain cell activity increases levels of key ingredient in Alzheimer's plaques

Washington University School of Medicine

Increased communication between brain cells increases levels of amyloid beta, the key ingredient in Alzheimer's brain plaques, scientists at Washington University School of Medicine in St. Louis have found.

The findings showed that turning up brain cell firing rates drove up levels of amyloid beta in the spaces between brain cells. Corresponding drops in amyloid beta levels occurred when brain cells' ability to send messages was dampened or blocked completely.

The results, produced in mouse models of Alzheimer's, will appear in the journal Neuron on Dec. 22. They complement a Washington University study published earlier this year that used functional brain imaging to show that the brain areas that develop Alzheimer's plaques are also the regions that are the most active in healthy young people who are daydreaming or not carrying out a specific cognitive task (http://news-info.wustl.edu/news/page/normal/5621.html).

The two papers have researchers considering the possibility of someday slowing or preventing the development of Alzheimer's disease by using pharmaceuticals to selectively reduce some communication between brain cells. However, researchers still have to determine if increased levels of amyloid beta can be partially linked to particular classes of the nerve cell messengers and receptors that cells use to communicate with each other.

"Ideally, we will be hoping to find a drug or mechanism that could very specifically target the processes that lead to increased amyloid beta levels," says lead author John Cirrito, Ph.D., a postdoctoral research associate in neurology and psychology. "If we can identify these and find ways to modulate them, we'd have new ways of intervening in Alzheimer's disease."

Senior author David Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, says that the results do not contradict earlier studies that suggested crossword puzzles, exercise and other mental stimulation can reduce the chances of developing Alzheimer's disease.

According to Holtzman, their new results and the WUSTL study published earlier this year instead offer further evidence that "cognitive idleness is not good from the perspective of Alzheimer's risk." The lead author of the earlier study, published in The Journal of Neuroscience, was Randy Buckner, Ph.D., associate professor of psychology at the School of Arts and Sciences and associate professor of neurobiology and radiology at the School of Medicine.

Together, these two studies may provide an explanation why specific regions are vulnerable to this disease. Holtzman and Cirrito speculate that activities such as crosswords and exercise may increase activity in brain areas less likely to be damaged by Alzheimer's and cause a corresponding reduction in activity levels in the regions consistently damaged by Alzheimer's disease.

"Almost all neurological diseases involve selective vulnerability--only certain classes of nerve cells or nerve cells found in particular regions are affected," Holtzman says. "Why that vulnerability is so selective often can be very difficult to determine, and Alzheimer's disease is no exception."

Washington University researchers became interested in connections between nerve cell activity levels and amyloid beta production when they read a paper two years ago from researchers at Cold Spring Harbor Laboratory and the University of Chicago that linked increased activity in nerve cell cultures to increased levels of amyloid beta.

Cirrito had previously modified a technique known as microdialysis to enable repeated sampling and measurement of amyloid beta levels in the brains of mice genetically modified to model human Alzheimer's disease. With Holtzman, Steven Mennerick, Ph.D., associate professor of psychiatry, and others, Cirrito used direct electrical stimulation and a variety of injected compounds to turn nerve cell communication up and down in the brains of living mice. They assessed the resulting effect on amyloid beta levels once every 30 minutes.

Through a series of these experiments, researchers linked increased amyloid beta levels to the release of synaptic vesicles, small packets containing chemical messengers known as neurotransmitters. The primary way nerve cells send messages to each other is to release the vesicles waiting at the synapse, a structure where the arms of two nerve cells almost touch. The neurotransmitters cross the synapse and bind to receptors on the surface of the receiving nerve cell. Normal brain physiology produces amyloid beta and naturally clears it from the brain, so Cirrito conducted a series of follow-up experiments to try to get a sense for whether increased synaptic vesicle release was affecting amyloid beta production or clearance.

"It's probably not clearance, and the effect on production is probably pretty small," he says. "Instead, it appears that synaptic activity is regulating the amount of amyloid beta that gets released from inside brain cells, where amyloid beta is produced. We're going to follow up with studies of whether particular neurotransmitters can be linked to changes in amyloid beta levels."

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Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates brain ISF Aß in vivo. Neuron, Dec. 22, 2005.

Funding from the National Institutes of Health, the Alzheimer's Association, Eli Lilly and the MetLife Foundation supported this research.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

View online: http://mednews.wustl.edu/news/page/normal/6324.html?emailID=7540

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