18 March 2005. If you need a reason to get off the bench and work up a sweat, consider this: Increasing physical and mental activity dramatically lowers amyloid plaque deposition in a mouse model of Alzheimer's disease, according to a study presented last week by Sangram Sisodia from the University of Chicago at the AD/PD 2005 conference in Sorrento, Italy. Young mice given access to exercise wheels and toys showed changes in the expression of genes implicated in learning and memory, blood vessel growth, neurogenesis, and cell survival pathways. Moreover, Aβ-degrading enzymes appeared to be more active in the exercising mice. The results, which were published in the March 11 issue of Cell, provide a biochemical link between environment and Alzheimer's progression by showing that a modest change in the experience of young animals can decrease amyloid levels.
Exercise, whether mental or physical, seems to fend off Alzheimer's disease in humans (Teri et al., 2003). Likewise, other studies with adult AD mice and normal aging beagles have shown that switching the animals from standard-issue laboratory cages to surroundings where they can exercise and play improves cognitive function (Milgram et al., 2005; Arendash et al., 2004.). Also in Sorrento, researchers in Carl Cotman's group at the University of California, Irvine, reported that five months of voluntary exercise stimulated both neurogenesis and learning in the water maze of CRND8 APP-transgenic mice. These mice, too, had fewer amyloid deposits in their cortex and hippocampus, as well as lower brain Aβ levels.
To look for possible effects on amyloid metabolism early in life, first author Orly Lazarov and colleagues started with weanling AD mice, treating the animals to daily sessions in a large cage with running wheels, brightly colored tunnels, and toys. They collaborated with researchers from Stanford University, the University of Kentucky, and the University of Pittsburgh, to measure Aβ levels, plaque deposition, and gene expression profiles between the enriched mice and those that were left in standard laboratory cages.
Their results showed that young mice that were allowed to frolic had decreased levels of Aβ and fewer plaques. The stimulated mice displayed a two-fold higher activity of the Aβ-degrading enzyme neprilysin, suggesting they were better able to clear Aβ than the normally housed mice. In the group of six enriched mice, the three who spent the most time on the running wheel had the lowest levels of Aβ. It remains to be determined whether clearer brains are the cause or the result of the mice's propensity to exercise. At this point, the Cotman group ascribes the anti-amyloid effect they have observed more to reductions in APP processing than to increases in neprilysin and IDE. Follow-up studies will sort out this question.
In Sisodia's study, microarray analysis of hippocampal gene expression identified enrichment-specific changes in transcript level for genes involved in a variety of pathways including Aβ sequestration and cell survival. Some of the enriched animals showed upregulation of genes thought to protect against neurodegeneration, such as BDNF, and other transcripts known to be increased by exercise.
This study involved a small number of mice and no physiological or behavioral tests were performed, so it remains to be shown how the changes in plaque burden and gene expression relate to cognitive status. Also, it is not clear what aspects of a complex natural environment are replicated by running wheels and colored toys for caged mice. "The demonstration that environmental factors can alter Aβ deposition raises more questions than it answers," write Stanislav Karsten and Daniel Geschwind of UCLA in an accompanying preview. But, they say, the study opens a door to understanding the interplay of genetics and the environment in Alzheimer's disease.—Pat McCaffrey, Gabrielle Strobel.
Pat McCaffrey is a science writer in Newton, Massachusetts
Lazarov O, et al. Environmental enrichment reduces Ab levels and amyloid deposition in transgenic mice. Cell 2005 March 11;120:701-713. Abstract.
Karsten SL and Geschwind DH. Exercise your amyloid. Cell 2005 March 11; 120:572-574. Abstract.