Study finds exercise slows developments of Alzheimer's-like
brain changes in mice         

[JULY 12, 2005]  SILVER SPRING, Md. -- Physical activity appears to inhibit Alzheimer's-like brain changes in mice, slowing the development of a key feature of the disease, according to a new study. The research demonstrated that long-term physical activity enhanced the learning ability of mice and decreased the level of plaque-forming beta-amyloid protein fragments -- a hallmark characteristic of Alzheimer's disease -- in their brains.

A number of population-based studies suggest that lifestyle interventions may help to slow the onset and progression of Alzheimer's. Because of these studies, scientists are seeking to find out if and how physically or cognitively stimulating activity might delay the onset and progression of Alzheimer's. In this study, scientists have now shown in an animal model system that one simple behavioral intervention – exercise -- could delay, or even prevent, development of pathology like Alzheimer's by decreasing beta-amyloid levels.

Results of this study, conducted by Paul A. Adlard, Ph.D., Carl W. Cotman, Ph.D., and colleagues at the University of California, Irvine, were published in the April 27 issue of The Journal of Neuroscience. The research was funded in part by the National Institute on Aging, a component of the National Institutes of Health, U.S. Department of Health and Human Services. Additional funding was provided by the Christopher Reeve Paralysis Foundation.

To directly test the possibility that exercise (in the form of voluntary running) may reduce the cognitive decline and brain pathology that characterizes Alzheimer's disease, the study utilized a transgenic mouse model of Alzheimer's rather than normal mice. The transgenic mice begin to develop Alzheimer's-like amyloid plaques at around 3 months of age. Initially, young mice (6 weeks or 1 month of age) were placed in cages with or without running wheels for periods of either one month or five months, respectively. Mice with access to running wheels had the opportunity to exercise anytime, while those without the wheels were classified as "sedentary."

On six consecutive days after the exercise phase, the researchers placed each mouse in a Morris water maze to examine how fast the mouse could learn the location of a hidden platform and how long this information was retained. (This water maze task involves a small pool of water with a submerged platform that the mouse must learn how to find.) The animals that exercised learned the task faster. Thus the mice that used the running wheels for five months took less time than the sedentary animals to find the escape platform. The exercised mice acquired maximal performance after only two days on the task, while it took more than four days for the sedentary mice to reach that same level of performance. This suggests that exercise may help to offset learning and cognitive deficits present in Alzheimer's disease patients.

Next, the investigators examined tissues from the brains of mice that had exercised for five months. They compared the levels of plaques, beta-amyloid fragments and amyloid precursor protein, a protein found throughout the body and from which the beta-amyloid peptide is derived. In Alzheimer's disease, beta-amyloid fragments clump together to form plaques in the hippocampus and cerebral cortex, the brain regions used in memory, thinking and decision-making.

Compared with the sedentary animals, mice that had exercised for five months on the running wheels had significantly fewer plaques and fewer beta-amyloid fragments (peptides) in the cerebral cortex and hippocampus, approximately by 50 percent. Additional studies, of exercised animals at 10 weeks old, showed that the mechanism underlying this difference began within the first month of exercise.

"These results suggest that exercise -- a simple behavioral strategy -- in these mice may bring about a change in the way that amyloid precursor protein is metabolized," says D. Stephen Snyder, Ph.D., director of the etiology of Alzheimer's program in the National Institute on Aging's Neuroscience and Neuropsychology of Aging Program. "From other research, it is known that in the aging human brain, deposits of beta-amyloid normally increase. This study tells us that development of those deposits can be reduced and possibly eliminated through exercise, at least in this mouse model."

These findings follow another recent report of a link between an enriched environment and Alzheimer's-like brain changes. That study, published Orly Lazarov, Ph.D., and colleagues in the March 11 issue of the journal Cell, found that beta-amyloid levels decreased in the brains of another kind of transgenic mice when they were housed in groups and in environments that were enriched with running wheels, colored tunnels and toys.

"Both of these studies are exciting because they offer insight into one of the pathways through which exercise and environment might promote resistance to development of cognitive changes that come with aging and AD," Snyder notes. "It is as though exercise or environmental enrichment forces the metabolism of amyloid precursor protein through a pathway that is less harmful and might even be beneficial. Further research will help us to understand those mechanisms, to learn how much and what kind of exercise is best, and to see if these same effects occur in humans."

[Alzheimer's Disease Education and Referral news release]

For information on participation in an Alzheimer's disease clinical trial, visit http://www.clinicaltrials.gov/ (search for Alzheimer's disease trials) or the Alzheimer's Disease Education and Referral Center website at http://www.alzheimers.org. The center may also be contacted toll free at 1 [phone].

The Alzheimer's Disease Education and Referral Center is sponsored by the National Institute on Aging to provide information to the public and health professionals about Alzheimer's disease and age-related cognitive change and may be contacted at the website and phone number above for a variety of publications and fact sheets, as well as information on clinical trials.