4‐Methylumbelliferone Restores Age‐Related Changes in Perineuronal Nets, Memory, and Neuroinflammation

Aging-associated cognitive decline is closely linked to dysregulated glial activity and chronic neuroinflammation, which together constrain neuronal plasticity. Astrocytes and microglia are key regulators of the brain extracellular matrix (ECM), including perineuronal nets (PNNs), whose accumulation during aging contributes to reduced synaptic flexibility. Targeting ECM-glia interactions therefore represents a promising strategy to modulate neuroinflammatory and plasticity-related processes. Here, we investigated the effects of long-term oral administration of 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan and chondroitin sulfate synthesis, on glial reactivity, ECM remodeling, and cognitive function in aged mice (20-22 months). Aging was associated with PNN remodeling alongside pronounced astrocytic and microglial activation and infiltration of peripheral immune cells. Chronic 4-MU treatment reduced PNN accumulation to levels observed in younger (10-month-old) mice, indicating effective ECM remodeling. Notably, this was accompanied by a marked attenuation of astrocyte and microglial activation and a reduction in immune cell infiltration, suggesting a broad normalization of the neuroinflammatory milieu. Functionally, these glia-associated changes were paralleled by improved recognition memory, with treated aged mice performing at or above the level of younger controls. Long-term 4-MU administration was well tolerated, with no evident adverse effects. Together, our findings identify ECM modulation as a mechanism to regulate glial reactivity and neuroimmune interactions in the aging brain. By targeting hyaluronan-dependent pathways, 4-MU links ECM remodeling to suppression of neuroinflammation and restoration of cognitive function, highlighting its therapeutic potential in age-related neurodegenerative processes.