Sorrento: More Fun, Less Amyloid for Transgenic Mice
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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
References
Paper Citations
- Teri L, Gibbons LE, McCurry SM, Logsdon RG, Buchner DM, Barlow WE, Kukull WA, LaCroix AZ, McCormick W, Larson EB. Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA. 2003 Oct 15;290(15):2015-22. PubMed.
- Milgram NW, Head E, Zicker SC, Ikeda-Douglas CJ, Murphey H, Muggenburg B, Siwak C, Tapp D, Cotman CW. Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiol Aging. 2005 Jan;26(1):77-90. PubMed.
- Arendash GW, Garcia MF, Costa DA, Cracchiolo JR, Wefes IM, Potter H. Environmental enrichment improves cognition in aged Alzheimer's transgenic mice despite stable beta-amyloid deposition. Neuroreport. 2004 Aug 6;15(11):1751-4. PubMed.
Further Reading
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Primary Papers
- Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K, Sisodia SS. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005 Mar 11;120(5):701-13. PubMed.
- Karsten SL, Geschwind DH. Exercise your amyloid. Cell. 2005 Mar 11;120(5):572-4. PubMed.
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Comments
Baylor College of Medicine
The main point of commonality between our work on environmental enrichment and plaque deposition (Jankowsky et al., 2003) and that of Lazarov et al. is the demonstration that environment can substantially influence the level of amyloid and Aβ peptide in the brain, even in mice carrying a variant APP allele that is associated with autosomal-dominant AD. Collectively, these studies provide experimental evidence for many decades of epidemiological studies suggesting that non-genetic factors such as education, occupation, and lifestyle can influence the risk for developing dementia.
That our work and that of Lazarov et al. reach different outcomes as to the effect of environment on Aβ levels indicates to us that a lot of interesting biology remains yet to be discovered about how the production and/or clearance of Aβ is regulated in response to diverse forms of enriched housing.
Significant differences between the two studies include the gender of the mice and the design of the enriched setting in each experiment. Lazarov et al focused on males; we used females. Their study emphasized physical activity, and placed animals in the enriched setting for limited periods several times a week; our study was a more classic version of enrichment in which the animals stayed in the enriched cage full-time. Their study exposed animals to at most three other cagemates; our study provided social interaction with a large cohort of other animals. (I am unsure whether the authors put four or nine animals in the enriched cage together at one time, in which case each mouse in their study could have encountered up to eight other animals when placed into the enriched cage.) Finally, if I read the paper correctly, our enriched animals were given more space per mouse than theirs (625 cm2 vs. approx 175-400 cm2 for nine or four mice, respectively, despite a suggestion that our animals were overcrowded (Marx, 2005).
Thus, there is no fixed version of enrichment, and experimental designs can vary substantially from one study to the next. We believe that all of these variables could play a role in determining whether A-beta levels are increased or decreased by exposure to environmental stimulation, and that our two studies open the door for further investigation into the relative contribution of each factor.
We have completed a second study of enrichment in APP transgenic mice (currently under review) that should address the concerns about stress that were apparently raised by Sam Sisodia, and repeated by Jean Marx, about our initial experiment. We look forward to seeing this study in press so we may clarify our findings with the Alzheimer research community.
References:
Jankowsky JL, Xu G, Fromholt D, Gonzales V, Borchelt DR. Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J Neuropathol Exp Neurol. 2003 Dec;62(12):1220-7. PubMed.
Marx J. Alzheimer's disease. Play and exercise protect mouse brain from amyloid buildup. Science. 2005 Mar 11;307(5715):1547. PubMed.
University of South Florida
The informative paper by Lazarov and colleagues is a logical extension of our earlier study, wherein we showed that environmental enrichment to "aged" APPsw transgenic mice provides global cognitive improvement without reducing their already well-established brain Aβ deposition (Arendash et al., 2004). Although our study indicates that mechanisms independent of Aβ deposition are sufficient for behavioral benefit in “aged” AD transgenic mice, the Lazarov study shows that environmental enrichment begun at an early age has the capacity to reduce developing brain Aβ levels/deposition, perhaps in part through the elevated neprilysin activity they also report. It should be noted that the study was conducted only with male mice, so the extend to which the findings hold for females is an open question, especially in view of another study (Jankowsky et al., 2003) showing that a different enrichment protocol actually increases Ab deposition in female AD transgenic mice.
The authors present data showing that transgenic mice having higher physical (wheel-running) activity during the final month’s enrichment sessions had lower brain Aβ levels than lower activity mice in the same environment. Their suggestion that exercise plays a role in modulating Aβ deposition is one of several possible explanations for these results. First, the three mice with high activity were not randomly selected for that activity level, so their higher activity level could simply reflect lower brain Aβ levels. Second, housing four male mice per cage invariably results in one or two mice bullying the others, which could result in the bullies occupying the limited running wheels for a longer period of time, as well as stress in the bullied mice. Third, higher activity animals may have been those that benefited most from the social and cognitive activities also present in an enriched environment. Indeed, since all enrichment mice were housed socially (four per cage) while control mice were housed individually, social activity could have contributed to the effects reported in this paper, quite separate from exercise or physical activity.
Of course, the most important question resulting from the findings of Lazarov and colleagues is "Can long-term environmental enrichment protect AD transgenic mice against the cognitive impairment that they otherwise develop?" It should not be assumed that limiting brain Aβ levels/deposition necessarily translates into cognitive protection. As well, there are three components to an enriched environment: social activity, physical activity, and cognitive activity. If cognitive protection does occur in AD transgenic mice through early and long-term environmental enrichment, it would be important to determine the relative contribution of each of these three activities to that cognitive protection.
Although retrospective studies in humans have linked a higher level of social, physical, and/or cognitive activity to reduced risk of AD in later life, retrospective observations in humans cannot determine whether these activities are a promoter or merely a self-selected marker of intact cognition. Therefore, well-controlled future enrichment studies in AD transgenic mice could provide insight impossible to attain in humans regarding the potential of one’s life-long activities to protect against AD, and the mechanisms involved.
References:
Arendash GW, Garcia MF, Costa DA, Cracchiolo JR, Wefes IM, Potter H. Environmental enrichment improves cognition in aged Alzheimer's transgenic mice despite stable beta-amyloid deposition. Neuroreport. 2004 Aug 6;15(11):1751-4. PubMed.
Jankowsky JL, Xu G, Fromholt D, Gonzales V, Borchelt DR. Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J Neuropathol Exp Neurol. 2003 Dec;62(12):1220-7. PubMed.
The University of Chicago
Reply by Sangram Sisodia and Orly Lazarov
The cage-mates in our study were all littermates;
therefore three to four animals shared a cage in our enrichment
experiment. I agree that much more needs to be done to validate the
model and the outcomes.
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