In the 11 March 2005 issue of Cell, the researchers show that mice raised in a deluxe setting - large cages filled with running wheels, colored tunnels and multiple toys -- had much less of the beta-amyloid peptides that are characteristic of Alzheimer's disease deposited in their brains and far lower levels of these damaging peptides in their blood than genetically similar mice raised in a standard environment.
Mice from enriched settings also had more of an enzyme that breaks down amyloid as well as increased activity of several genes involved in learning and memory, brain cell survival and the growth of new blood vessels.
"We have plenty of epidemiological evidence connecting activity, exercise and education with later onset of Alzheimer's, but it has never been clear which came first," said study-author Sangram Sisodia, Ph.D., professor of neurobiology, pharmacology and physiology at the University of Chicago. "Did the active lifestyle delay disease, or was there something inherent in a disease-resistant brain that led to a mentally and physically active lifestyle?"
"This is the first demonstration," he said, "in a genetically clean, carefully controlled animal model showing that an enhanced environment can have such a tremendously beneficial impact, protecting the brain from the pathological hallmarks of this insidious disease."
These findings support a "potentially causal inverse relationship between a more engaging, enriched life and AD progression," note Stanislav Karsten and Daniel Geschwind of UCLA in an accompanying editorial. They also provide "clear initial directions for exploring the role of the environment and the molecular pathways perturbed in AD and other neurodegenerative disorders."
Sisodia, assisted by Orly Lazarov and John Robinson at the University of Chicago and colleagues at Stanford, Pittsburgh, Pennsylvania and Kentucky, studied mice carrying two distinct genes (amyloid precursor protein and presenilin-1) that predispose the animals to develop Alzheimer's early in life.
At one month of age, nine of these mice were placed in the enriched environment and seven in standard housing. After five months, the researchers began to search for the pathological signs of AD in the mice's brains.
They found that mice from the enriched environment had a dramatic reduction of amyloid deposits in their brains, including less than half the volume of amyloid deposits in the hippocampus and cortex, regions involved in memory and reasoning.
The researchers also looked for genes that were activated at different levels in brains of mice from enriched versus standard housing. They identified 41 such genes, many of them already known to protect nerve cells. One of them was the gene for an enzyme that degrades beta-amyloid called neprilysin, which was at significantly higher levels in mice from the enhanced setting.
These mice also showed greater activity for several other genes involved in memory and learning, the growth of new nerve cells, cell survival, and the growth of new blood vessels within the brain.
The researchers also noted one "personality" difference among the mice in the enriched environment that influenced amyloid levels. Some of these mice were extremely active, frequently exploring their cages or running on the wheel. Others, the couch-potato mice, had the same opportunities for exercise but chose much less activity.
The most active mice had the least beta-amyloid. Less active mice from the enriched environment had more and those from the standard housing, who got the least exercise, had the most.
A lot of the process involves simple plumbing, Sisodia suspects, delivering blood to the brain and carrying harmful substances away. "It may be all about blood flow," he suggested. Exercise and mental activity can stimulate growth of new vessels while they help keep existing vessels in the brain open and functional, just like in the heart.
"Whenever we find amyloid deposits in the brain we also see them in the vessels," he said. "We suspect a large part of this process is the growing inability of mice, or people, who are developing Alzheimer's to get rid of the substances that comprise amyloid deposits, to slice up the peptides, sweep them into the blood stream and ship them out of the brain."
The take home message for humans, he said, is use it or lose it. "Activity helps, physical activity helps and mental activity helps," he said, "and the earlier you begin the better, a troubling notion in an increasingly inactive society. This is prevention, not therapy."
About 4.5 million people in the United States have Alzheimer's disease, including about five percent of those aged 65 to 74. Risk increases with age.
The National Institutes of Health, the Ellison Medical Research Foundation and the Alzheimer's Association funded this study. Additional authors include first author Orly Lazarov, John Robinson and Ya-Ping Tang of the University of Chicago; Ilana Hairston and Robert Sapolsky of Stanford; Zeljka Korade-Mirnics and Karoly Mirnics of the University of Pittsburgh; Virginia Lee of the University of Pennsylvania; and Lou Hersh of the University of Kentucky.