Oral 4-methylumbelliferone remodels brain extracellular matrix and improves memory in aged mice

In aged mice between 20 and 22 months old, brain aging is marked by perineuronal net accumulation, elevated glial activation, and peripheral immune cell infiltration. Researchers gave these mice long-term oral 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan and chondroitin sulfate synthesis, to investigate its effects on brain extracellular matrix remodeling and neuroinflammation. The treatment reduced perineuronal net accumulation to levels seen in 10-month-old mice. Chronic 4-MU also blunted astrocyte and microglial activation and decreased immune cell infiltration. Along with these extracellular and neuroinflammatory changes, treated aged mice showed improved recognition memory, performing at or above the level of younger control animals. The regimen was well tolerated, with no evident adverse effects.