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

December 21, 2005

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 (

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."
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:

Washington University School of Medicine

Related Nerve Cells Articles from Brightsurf:

Nerve cells let others "listen in"
How many ''listeners'' a nerve cell has in the brain is strictly regulated.

Nerve cells with energy saving program
Thanks to a metabolic adjustment, the cells can remain functional despite damage to the mitochondria.

Why developing nerve cells can take a wrong turn
Loss of ubiquitin-conjugating enzyme leads to impediment in growth of nerve cells / Link found between cellular machineries of protein degradation and regulation of the epigenetic landscape in human embryonic stem cells

Unique fingerprint: What makes nerve cells unmistakable?
Protein variations that result from the process of alternative splicing control the identity and function of nerve cells in the brain.

Ragweed compounds could protect nerve cells from Alzheimer's
As spring arrives in the northern hemisphere, many people are cursing ragweed, a primary culprit in seasonal allergies.

Fooling nerve cells into acting normal
In a new study, scientists at the University of Missouri have discovered that a neuron's own electrical signal, or voltage, can indicate whether the neuron is functioning normally.

How nerve cells control misfolded proteins
Researchers have identified a protein complex that marks misfolded proteins, stops them from interacting with other proteins in the cell and directs them towards disposal.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Research confirms nerve cells made from skin cells are a valid lab model for studying disease
Researchers from the Salk Institute, along with collaborators at Stanford University and Baylor College of Medicine, have shown that cells from mice that have been induced to grow into nerve cells using a previously published method have molecular signatures matching neurons that developed naturally in the brain.

Bees can count with just four nerve cells in their brains
Bees can solve seemingly clever counting tasks with very small numbers of nerve cells in their brains, according to researchers at Queen Mary University of London.

Read More: Nerve Cells News and Nerve Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to