Enriched environment reduced Alzheimer’s dangerous peptides in mice

A research group based at the University has found that an enriched environment—in this case, more chances to exercise, explore and interact with others—can dramatically reduce the biological hallmarks of Alzheimer’s disease in mice that are genetically predisposed to the disorder.

In the Friday, March 11 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 than genetically similar mice raised in a standard environment.

Mice from enriched settings also had more of an enzyme that breaks down beta-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, Professor in Neurobiology, Pharmacology & Physiology. “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 the University of California, Los Angeles, in an editorial that accompanied the research article.

Lead author of the study Orly Lazarov, Research Associate and Assistant Professor in Neurobiology, Pharmacology & Physiology, and John Robinson, Senior Research Technician in Neurobiology, Pharmacology & Physiology, and their team of researchers studied mice carrying two mutated, distinct genes (amyloid precursor protein and presenilin-1) that predispose the animals to develop Alzheimer’s disease early in life.

At 1 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 Alzheimer’s disease in the mice 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 the cortex, the regions involved in memory and reasoning.

The researchers also looked for genes that were activated at different levels in the brains of mice from enriched vs. 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 detected at significantly higher levels in mice exposed to 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 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 beta-amyloid than the most active mice, and those from the standard housing that got the least exercise had the highest levels of the peptides.

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 message for humans is “use it or lose it,” he said. “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 5 percent of those between 65 and 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 of the paper are Ya-Ping Tang, Assistant Professor in Psychiatry; Ilana Hairston and Robert Sapolsky of Stanford University; 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.