In many studies that have been carried out on humans and on animals, it has been suggested that stress can increase the risk of Alzheimer's disease. This new research is the first in many studies that shows the basic biomolecular mechanisms that may underlie this increased risk.

Co authors John G. Csernansky, MD, the Gregory B. Couch Professor of Psychiatry and Professor of Neurobiology, and Hongxin Dong, Ph.D., Instructor of Psychiatry at Washington University in Saint Louis did earlier studies that revealed that using mice genetically modified to emulate human Alzheimer's disease, as well as raising the mice under isolated conditions in smaller cages did accelerate the deposition of brain plaques made up of a peptide known as amyloid beta, and declines in cognitive ability.

This led the researchers to believe that stress was raising amyloid beta levels. But because other factors can also speed up plaque buildup, the researchers had to test the link by using a technique known as microdialysis. They monitored amyloid beta in mice brains exposed to the same stressors -- isolation and smaller cages.

David Holtzman, MD and the Andrew B. and Gretchen P. Jones Professor of Neurology and Molecular Biology & Pharmacology -- also head of the Department of Neurology at WU, the Associate Director of the Alzheimer's Disease Research Center, and a member of the Hope Center for Neurological Disorders stated that stress did, in fact, elevate soluble amyloid beta levels in the spaces between brain cells. But based on those initial experiments, Holtzman and his colleagues were not sure if it was a chronic effect or a much more immediate effect.

They felt that if it was more immediate, they might be able to identify some of the brain molecules involved in increasing the levels. Jea-Eun Kang, lead author, and a graduate student in the Holtzman laboratory devised a faster way to create stress by temporarily restraining the mice so that they could not move. Three hours of restraint led to a 30% increase in amyloid beta levels. This encouraged the researchers to start looking for molecules that might be enabling this rapid change.

Stress hormones produced by the adrenal gland were natural suspects. In mice, that is corticosterone, which is the mouse equivalent of the human hormone cortisol. But a large dose of corticosterone didn't cause a similar rapid change in amyloid beta levels.

The scientists then broadened their search for molecules released in the mouse brain by stress, and identified one called corticotropin-releasing factor (CRF). CRF is linked to increased levels of brain cell communication. In 2005, Holtzman, John Cirrito, Ph.D., a postdoctoral research associate in neurology and psychiatry, and colleagues showed that increased communication between brain cells also contributed to increased amyloid beta. Placing CRF in the brains of mice, showed amyloid beta levels immediately rising and mice given a CRF blocker followed by a stressful situation did not display an increase in amyloid beta.

When they directly placed CRF in the mouse brain, amyloid beta levels rose immediately. Mice given a CRF blocker and then stressed did not display increased amyloid beta. This led Holtzman to note that "head trauma increases risk, higher education lowers it. Stress may be another environmental factor that increase the risk."

Holtzman, Csernansky and colleagues are intrigued by the possibility that drugs that block CRF or reduce anxiety may provide a new way to decrease amyloid beta and eventually delay or prevent Alzheimer's disease. They are continuing to explore connections between brain cell activity and amyloid beta levels.

The studies were carried out in the Hope Center for Neurological Disorders and in conjunction with the Alzheimer's Disease Research Center, both at Washington University School of Medicine.

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