UNDERSTANDING THE EFFECTS OF ENVIRONMENTAL ENRICHMENT ON MICROGLIA IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

Environmental enrichment (EE) provides a multimodal combination of sensory, social, cognitive, and motor stimulation that enhances brain activity and has shown beneficial effects in models of Alzheimer’s disease (AD). Microglia, the brain’s frontline immune sensors, support tissue homeostasis under physiological conditions. However, during AD progression, microglia shift from early protective amyloid-β (Aβ)–clearing responses to dysfunctional states that contribute to neurodegeneration. Notably, microglial behavior is influenced by environmental and lifestyle-related factors, including social interaction and physical activity, which have emerged as potential modulators of disease progression. In this study, we investigated the role of microglia in mediating the effects of EE in a mouse model of AD using a microglial depletion strategy. Wild-type (WT) and 5xFAD mice were housed under standard or enriched conditions and treated with either a control diet or a PLX3397-containing diet, a colony-stimulating factor 1 receptor (CSF1R) inhibitor that depletes microglia. We first assessed AD-associated cortical changes in pre- and postsynaptic markers and examined how these changes were modulated by EE and microglial phagocytic activity. In parallel, we analyzed microglial interactions with amyloid aggregates. Our results show that EE attenuated the loss of VGLUT1⁺ presynaptic structures in 5xFAD mice and was associated with reduced microglial engulfment of VGLUT1⁺ puncta. Furthermore, EE promoted recruitment of microglia around Aβ plaques and induced increased amyloid engulfment compared to standard housing. Overall, these findings suggest that the beneficial effects of EE observed on synapses and Aβ deposits in 5xFAD mice are, at least partially, mediated by microglia.