Physical activity appears to inhibit Alzheimer's

Physical activity appears to inhibit Alzheimer's-like brain changes in mice, slowing the development of a key feature of the disease, according to new research.

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 (AD)--in their brains.

A number of population-based studies suggest that lifestyle interventions may help to slow the onset and progression of AD. 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 disease. 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 AD-like pathology 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, are published in the April 27, 2005, issue of The Journal of Neuroscience. The research was funded in part by the National Institute on Aging (NIA). 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 AD, the study utilized a transgenic mouse model of AD rather than normal mice. The transgenic mice begin to develop AD-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 1 month or 5 months, respectively. Mice with access to running wheels had the opportunity to exercise any time, while those without the wheels were classified as "sedentary."

On 6 consecutive days after the exercise phase, the researchers placed each mouse in a Morris water maze to examine how fast it could learn the location of a hidden platform and how long it retained this information. (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 5 months took less time than the sedentary animals to find the escape platform. The exercised mice acquired maximal performance after only 2 days on the task, while it took more than 4 days for the sedentary mice to reach that same level of performance. This suggests that exercise may help to offset learning/cognitive deficits present in AD patients.

Next, the investigators examined tissues from the brains of mice that had exercised for 5 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 AD, 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 to the sedentary animals, mice that had exercised for 5 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 NIA'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, 2005, 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."