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

Aging leads to cognitive decline due to reduced neuronal plasticity and increased brain inflammation. Disruption of perineuronal nets (PNNs) is a recognized strategy to enhance neuroplasticity. Hyaluronan forms the backbone of PNNs, and 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, has been proposed to disrupt PNNs and enhance neuroplasticity in young rodents. In addition, 4-MU is also known as an immune response regulator, although its effects within the central nervous system (CNS) have been less characterized. In this study, we investigated the impact of long-term oral 4-MU administration in aged mice (20-22 months old), focusing on PNNs intensity, memory, and neuroinflammation. PNN intensity increased with age, and 4-MU treatment reduced it in 22-month-old mice to levels observed in 10-month-old animals; in the novel object recognition test, treated 22-month-old mice performed comparably to or better than 10-month-old controls. Moreover, markers of aging-associated neuroinflammation--including astrocytic and microglial activation as well as peripheral immune cell infiltration--were normalized to 10-month-old levels or further diminished following 4-MU treatment. Importantly, chronic 4-MU administration was well tolerated in aged mice, with no serious adverse effects observed. Together, these results suggest that 4-MU mitigates PNNs accumulation and neuroinflammaging while enhancing recognition memory, supporting its potential as a safe therapeutic approach for age-related cognitive decline.