St. Louis, June 4, 2007 — Scientists revealed in November 2006 that stress increases production in mice of a brain peptide critical to Alzheimer's disease. Now the same group has shown that blocking a different brain peptide slows the stress-induced increase, opening a new door to treatment. Researchers from Washington University School of Medicine in St. Louis report the results online this week in the Proceedings of the National Academy of Sciences.
Studies of humans and animals have suggested that stress may increase risk of Alzheimer's disease, but the new research is among the first studies to elaborate the basic biomolecular mechanisms that may underlie this increased risk.
The results build on earlier findings from coauthors John G. Csernansky, M.D., the Gregory B. Couch Professor of Psychiatry and professor of neurobiology, and Hongxin Dong, Ph.D., instructor in psychiatry. Using mice genetically modified to model human Alzheimer's disease, Csernansky and Dong showed that raising them under isolated conditions in smaller cages accelerated the deposition of brain plaques and declines in cognitive ability.
Brain plaques are believed to be a primary cause of the memory loss and other mental damage inflicted by Alzheimer's disease. They are mostly comprised of a peptide known as amyloid beta, so researchers immediately suspected that stress was increasing amyloid beta levels. But because there are other factors that can accelerate plaque build-up, they needed to test the link.
For that new test, scientists used a technique known as microdialysis to monitor amyloid beta levels in the brains of mice exposed to the same stressors: isolation and smaller cages.
"Stress remarkably elevated soluble amyloid beta levels in the spaces between brain cells," says senior author David Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. "But we didn't know based on those initial experiments if it was a chronic effect or a much more immediate effect. If it was more immediate, we thought we might be able to identify some of the brain molecules involved in increasing the levels."
Lead author Jea-Eun Kang, a graduate student in the Holtzman lab, utilized a quicker way to cause stress: temporarily restrain mice from moving. Three hours of restraint led to a 30 percent increase in amyloid beta levels.
The spike in amyloid beta encouraged 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 meant corticosterone, 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.
When they widened their search for molecules released in the mouse brain by stress, the scientists identified one called corticotropin-releasing factor (CRF), which 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.
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.
"There are very few known environmental risk factors for Alzheimer's disease," Holtzman notes. "Head trauma increases risk, higher education lowers it. Stress may be another environmental factor that increases risk."
Holtzman, Csernansky and their 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. Holtzman and his colleagues are also 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.
Kang J-E, Cirrito JR, Dong H, Csernansky JG, Holtzman DM. Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and neuronal activity. Proceedings of the National Academy of Science, electronic edition, June 4, 2007.
Funding from the National Institute on Aging of the National Institutes of Health, the Alzheimer's Association, the Cure Alzheimer's Fund and Eli Lilly 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 fourth 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.
Journal
Proceedings of the National Academy of Sciences