Karsten SL, Geschwind DH.
Exercise your amyloid.
Cell. 2005 Mar 11;120(5):572-4.
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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.
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.
Reply by Sangram Sisodia and Orly LazarovThe 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.