Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms

Lifelong cognitive stimulation is associated with a lower risk of Alzheimer's disease (AD), but causality is difficult to prove. We therefore sought to investigate the preventative potential of environmental enrichment (EE) using mice expressing both human mutant presenilin-1 and the amyloid precursor protein (PS1/PDAPP). At weaning, mice were placed into either an enriched or standard housing environment. Behavioral testing at 4.5–6 months showed that environmentally enriched PS1/PDAPP mice outperformed mice in standard housing, and were behaviorally indistinguishable from non-transgenic mice across multiple cognitive domains. PS1/PDAPP mice exposed to both environmental enrichment and behavioral testing, but not to EE alone, showed 50% less brain β-amyloid without improved dendritic morphology. Microarray analysis revealed large enrichment-induced changes in hippocampal expression of genes/proteins related to Aβ sequestration and synaptic plasticity. These results indicate that EE protects against cognitive impairment in AD transgenic mice through a dual mechanism, including both amyloid dependent and independent mechanisms.