4-methylumbelliferone attenuates amyloid pathology and learning deficits in the APP/PS1 mouse model

4-Methylumbelliferone (4-MU) inhibits hyaluronic acid (HA) synthesis and is currently approved in Europe for biliary spasm. 4-MU administration reduces perineuronal nets (PNNs), and enzymatic degradation of PNNs in mouse models of Alzheimer’s disease (AD) attenuates memory impairment. Although 4-MU has therapeutic efficacy in rodent models of fibrosis and cancer, it has not been examined in an Alzheimer’s model. Here, we evaluated the impact of long-term 4-MU treatment in the APP/PS1 amyloid mouse model. From three months of age, mice were on either a vehicle or 4-MU–supplemented diet for 70 days or 52 weeks. Short and long-term 4-MU treatment decreased the soluble parenchymal Aβ _1-42 /Aβ _1-40 ratio. Reductions in insoluble amyloid plaque were observed following 52 weeks of treatment. Extended 4-MU administration also reduced PNN intensity and ameliorated spatial memory deficits in APP/PS1 mice. These findings provide support for targeting brain extracellular matrix (ECM) as a therapeutic strategy for AD.