Levels of b-amyloid peptides, which clump together to form the brain "tangles" or plaques that are toxic to nerve cells in Alzheimer's disease, were significantly lower in the enriched mice, say Sangram Sisodia, of the University of Chicago, and colleagues. The enriched mice may have been better equipped than their less-stimulated counterparts to sweep these peptides out of the brain, according to the researchers' analysis of gene and enzyme expression in the animals.
"This goes back to the old idea of use it or lose it, that using your brain keeps it more active," Sisodia says. "It's more common sense than anything, but what we didn't previously appreciate is that it might affect the pathology that is characteristic of Alzheimer's disease."
The experiments in mice suggest that the enriched environment acts as a protective factor, keeping peptide levels low before they can aggregate and cause problems, rather than a therapeutic factor that dissolves plaques that have already formed, Sisodia says.
The researchers also found intriguing clues that an active body, as well as an active brain, might be a key factor in reaping the benefits of an enriched environment. The most physically active of the mice in the elaborately furnished cages had the most dramatic reductions in amyloid peptides and deposits. At least among this small group of mouse workout devotees, "exercise appears to play a significant role in modulating amyloid deposition," Sisodia and colleagues write.
The researchers caution, however, that it will take more experiments with larger numbers of animals to determine exactly how enriched environments benefit mice, whether through increased physical activity, a boost in visual, social, and spatial stimuli that awaken the brain, or some combination of all of these factors.
Sisodia says exercise, along with any kind of mental activity from reading to doing the crossword puzzle, are probably the equivalent of chew toys and running wheels for humans. "It's all very important in keeping the mind active and potentially staving off effects of old age."
The b-amyloid peptides found in Alzheimer's are snippets of a larger protein called amyloid precursor protein. Researchers are still debating whether the b-amyloid peptides themselves or the plaques they form are the major cause of Alzheimer's disease symptoms.
Sisodia and colleagues were intrigued by recent research suggesting that connections between brain cells change throughout life in response to new environments, and that activity at these communication hubs can affect the production of b-amyloid peptides. They decided to see if mice raised in different environments would produce different levels of the peptides.
The researchers placed nine newly weaned mice that had been genetically engineered to resemble humans with early-onset Alzheimer's disease into cages filled with tunnels, toys, and other objects for five months. Seven similarly engineered mice were kept in less lavishly furnished cages as a comparison group.
The enriched mice had higher levels of an enzyme called neprilysin that destroys b-amyloid peptides, the researchers found. After analyzing DNA from the two groups of animals, Sisodia and colleagues also discovered that a number of genes were more active in the enriched group. Some of these genes encode proteins involved in learning and memory, new blood vessel formation, nerve cell protection, and molecular mechanisms to isolate and discard b-amyloid peptides, the researchers discovered.
Sisodia believes these genes may hold clues to exactly how the enriched mice were able to lower their b-amyloid peptide levels. For instance, genes for new blood vessel formation may speed the movement of b-amyloid peptides out of the brain into the circulating blood plasma, he says.
The researchers plan to study these genes further to find out exactly how their expression might affect b-amyloid peptide levels. Sisodia and colleagues also want to look at how enriched environments might benefit mice that already have advanced Alzheimer-like symptoms.
According to the group Alzheimer's Disease International, as many as 18 million people around the world suffer from the disease. In the United States, about 4.5 million people have Alzheimer's disease. The disease usually occurs in people age 60 and older, and risk increases with age. According to the National Institute on Aging, about five percent of Americans ages 65 to 74 have Alzheimer's disease.
The other members of the research team include Orly Lazarov, John Robinson, and Ya-Ping Tang of the University of Chicago, Ilana S. Hairston and Robert M. Sapolsky of Stanford University, Virginia M.-Y. Lee of the University of Pennsylvania School of Medicine, Louis B. Hersh of the University of Kentucky, and Zeljka Korade-Mirnics and Karoly Mirnics of the University of Pittsburgh. The study was supported in part by the National Institutes of Health, the National Institute on Drug Abuse, the National Institute on Aging, the Ellison Medical Research Foundation, the Alzheimer's Association, and the Adler Foundation.
Orly Lazarov, John Robinson, Ya-Ping Tang, Ilana S. Hairston, Zeljka Korade-Mirnics, Virginia M.-Y. Lee, Louis B. Hersh, Robert M. Sapolsky, Karoly Mirnics, and Sangram S. Sisodia: "Environmental Enrichment Reduces A(beta) Levels and Amyloid Deposition in Transgenic Mice"
Publishing in Cell, Volume 120, Number 5, March 11, 2005, pages 701-713. http://www.cell.com
Journal
Cell