Preventive and therapeutic types of environmental enrichment counteract beta amyloid pathology by different molecular mechanisms

Combined preventive and therapeutic physical/cognitive stimulation starting before disease onset and continuing over its progression reduce Alzheimer-related pathology in transgenic mice. We now report that exposure of TgCRND8 mice to an enriched environment as either a preventive or therapeutic approach is also capable to reduce Aβ burden, though with different plaque and cerebral amyloid angiopathy (CAA) morphology. Preventive treatment resulted in fewer and smaller plaques without affecting CAA, whereas in therapeutically treated mice beside reduction of CAA extent, numerous plaques of strongly diminished size were found, so that total plaque loads declined as well. These effects seemed to be mediated by distinct molecular pathways. In preventive but not therapeutic group a shift of Aβ(42/40) ratio towards Aβ(40) and up-regulation of Aβ clearing and degrading molecules were found. Contrariwise anti-oxidative defense mechanisms were induced only in therapy but not preventive group. We hypothesize that preventive enrichment lowers the amounts of plaque seeds and decelerates plaque growth by degradation and clearance of Aβ, while therapeutic enrichment mitigates growth and fusion of plaque seeds to large plaques by inhibiting further Aβ aggregation. This study provides an experimental basis for application of physical/cognitive training in both prophylaxis and therapy of Alzheimer's disease.