Enriched Environment Alleviate AD Pathological Progression by Reducing Microglia Complement Signaling in Aged Male APP/PS1 Mice

ABSTRACT Alzheimer's disease (AD) is influenced by genetic and environmental factors. Previous studies showed that enriched environments improved memory and reduced amyloid plaques in AD mice, but the underlying mechanisms remain unclear. This study investigated the effects and mechanisms of enriched environments on AD pathology and cognitive function in aged APP/PS1 mice. Male APP/PS1 mice (15 months old) and wild‐type littermates were divided into four groups: WT/SE, WT/EE, Tg/SE, and Tg/EE. Mice in EE groups were subjected to intervention with enriched environment for a period of 5 months. Results showed that enriched environments preserved cognitive function, reduced Aβ and p‐Tau aggregation, and mitigated microglial inflammation (Tlr‐4, NF‐κB, iNOS). They also decreased C1q expression and slowed dendritic spine loss in hippocampal granule cells of APP/PS1 mice. These findings suggest that enriched environments can slow AD progression by regulating microglial inflammation and maintaining neuronal integrity, particularly in hippocampal dendritic spines.