Limited Effects of Prolonged Environmental Enrichment on the Pathology of 5XFAD Mice

The environmental enrichment (EE) paradigm is regarded as a useful tool to create a physical and intellectual stimulation for laboratory rodents and has been used in a variety of Alzheimer disease (AD) mouse models. However, the results of these studies have been conflicting as EE had inconsistent effects on memory performance, Aβ deposition, inflammatory status and other pathological outcomes depending on the AD model. Here, we studied the influence of a lifelong EE on the widely used 5XFAD mouse model, representing the main pathological features of AD. Although 11 months of enriched housing led to an improved survival rate and a partial rescue of motor performance, no beneficial effects in terms of anxiety phenotype, working memory performance, Aβ plaque load, Aβ_1-42 levels, endogenous APP processing and inflammatory status were observed in 5XFAD mice. Concordantly, no changes in expression levels of BACE1 or Aβ-degrading enzymes like neprilysin or insulin-degrading enzyme could be detected in active mice. The 5XFAD model develops a relatively fast and aggressive pathology and therefore presents a model for early onset familial AD. Our results suggest that an intervention like EE might be too mild to counteract the fast disease progression seen in this model. Therefore, our data provide evidence that the effects of physical and cognitive stimulation vary depending on the severity of the pathology of the model and therefore might be more beneficial in models developing a milder AD phenotype.