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

Abstract

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 (4MU), an inhibitor of hyaluronan synthesis, has been proposed to disrupt PNNs and enhance neuroplasticity in young rodents. In addition, 4MU 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 4MU administration in aged mice (20 to 22 months old), focusing on PNNs intensity, memory, and neuroinflammation. PNN intensity increased with age, and 4MU 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 4MU treatment. Importantly, chronic 4MU administration was well tolerated in aged mice, with no serious adverse effects observed. Together, these results suggest that 4MU mitigates PNNs accumulation and neuroinflammaging while enhancing recognition memory, supporting its potential as a safe therapeutic approach for age related cognitive decline.