Researchers have uncovered the pathways behind the protection offered by environmental stimulation in Alzheimer’s disease, further confirming that enhanced mental and physical activity slows neurological decline. The paper by Ambrée et al., "Reduction of amyloid angiopathy and A² plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways," appears in the August issue of The American Journal of Pathology.
Alzheimer’s disease, the leading cause of senile dementia, presents with cognitive and behavioral deficiencies resulting in part from accumulation of b-amyloid (Ab) deposits within the brain (Ab plaques) and its blood vessels (amyloid angiopathy). Although previous studies have shown that increased mental and physical activity can slow the progression of the disease, how such deceleration occurs has been unclear until now.
Dr. Kathy Keyvani’s group at University Hospital Muenster examined the effects of environmental stimulation on the brain pathology of TgCRND8 mice. These mice, which express a mutant form of Ab found in some Alzheimer’s patients, develop Alzheimer-like features including Ab plaques and cognitive deficits. To study the effects of enrichment, mice were housed in either standard cages or enriched cages, similar to the standard but with access to a stimulus cage containing permanent fixtures (rope and gnawing wood) as well as removable items (tunnels, balls, ladders, ramps, and exercise wheels) that were changed on a rotating basis.
Following five months of standard versus enriched housing, mouse brains were examined for signs of disease. Mice housed in the enriched environment had fewer Ab plaques, smaller plaque size, and reduced amyloid angiopathy compared to mice housed in standard cages. Interestingly, there were no differences in the levels of soluble Ab peptide or the transcriptional/translational expression levels of its precursor protein (APP) or the processing of APP between the two groups. So how did environmental stimulation prevent disease?
To answer this question, Ambrée et al. performed DNA microarray analysis to determine which genes were differentially regulated in mice housed in the enriched environment compared to standard cages. Enriched mice exhibited down-regulation of pro-inflammatory genes but up-regulation of genes related to anti-inflammatory processes, protein degradation and cholesterol binding. These results were confirmed by specifically analyzing gene expression for examples in each category. Together these data suggest that an enriched environment elicits protection via pathways that prevent Ab accumulation and enhance its clearance.
The authors speculate that the altered expression of inflammatory genes may shift the immune response from one that is neurotoxic to one that is phagocytic, i.e., able to clear unwanted debris, such as Ab. In accordance with this, a significant enhancement of microglial activity was found by Western blot and morphometric analyses of microglia, which often surround and infiltrate Ab plaques. In addition, activating cellular protein degradation pathways provides another means of removing excess Ab. Finally, changes in cholesterol homeostasis, elements of which have been shown to correlate with Ab deposition, may exert beneficial effects by preventing plaque formation in the first place.
These data provide strong evidence that an environment rich in mental and physical stimulation slows the progression of Alzheimer-like brain pathology. Further investigation of the pathways and individual elements involved in such protection may provide novel treatment strategies for Alzheimer’s disease. Until that time, keep your running shoes and crossword puzzles handy.
This work was supported by grants from Innovative Medical Research and German National Academic Foundation.
Work was directed by Dr. Kathy Keyvani of University Hospital Muenster and involved collaborators at University of Muenster.
Ambrée O, Leimer U, Herring A, Görtz N, Sachser N, Heneka MT, Paulus W, Keyvani K. Reduction of amyloid angiopathy and A² plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am J Pathol 2006 169:544-552
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