The role of microglia in mediating the beneficial effects of environmental enrichment in neurodegenerative diseases and dementia

• Microglia shape neurodegeneration and are key therapeutic targets. • Environmental enrichment enhances neuroplasticity and neuroimmune regulation. • EE–microglia interactions may drive beneficial effects in neurodegenerative diseases. Neurodegenerative diseases are characterized by a variety of pathogenic processes, including various forms of protein aggregation that disrupt neural homeostasis and ultimately lead to functional decline. With an aging population, the prevalence and associated economic burden of these diseases are expected to rise dramatically, underscoring the urgent need for effective therapies. Protein aggregation, a hallmark of Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), activates microglia, the brain’s resident immune cells. While microglia help maintain homeostasis, their overactivation exacerbates synaptic loss and network disruption, making them key players in neurodegenerative pathology and potential therapeutic targets. Environmental enrichment (EE), a laboratory paradigm that enhances experience-dependent plasticity through physical, sensory and cognitive stimulation, has been shown to produce beneficial molecular, cellular, and behavioural outcomes in rodent models of neurodegeneration, including modulation of microglial activity. This review highlights current findings on the effects of EE on microglia across different neurodegenerative diseases. However, collective results remain limited due to variations in EE paradigms such as differences in duration, timing, and enrichment setup, which hinder direct comparisons. Moreover, most studies have focused on AD, with far fewer investigations in other neurodegenerative conditions. Current findings are largely descriptive, examining microglial density, activation state, morphology, and gene expression, without establishing causative relationships. Future research should determine whether microglial depletion alters the beneficial effects of EE, thereby clarifying the complex interplay between EE, microglia, and neurodegenerative pathology. Such studies will be essential for identifying therapeutic strategies that harness EE to modulate microglia and mitigate disease progression.