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 approved in Europe for treatment of biliary spasm. 4-MU administration reduces perineuronal net (PNN) levels, 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 Aβ1-42/Aβ1-40 ratio. Reductions in insoluble amyloid plaque were observed following 52 weeks of treatment.

Moreover, extended 4-MU administration reduced PNN intensity and ameliorated spatial memory deficits in APP/PS1 mice. These findings demonstrate that chronic 4-MU treatment produces coordinated alterations in HA and ECM composition, amyloid pathology, and spatial learning behavior in APP/PS1 mice. Together, these findings support further investigation of pharmacological ECM modulation as a potential therapeutic strategy for AD, while recognizing that the present study does not establish a causal relationship between ECM remodeling, amyloid pathology, and cognitive improvement.

Further studies are needed to define the mechanisms underlying the effects of 4-MU on amyloid pathology and cognitive function. The authors would like to acknowledge support from the Department of Comparative Medicine The authors would like to acknowledge funding from the National Institutes of Health (AG077002; KC) and (AG071745; MA). Department of Neuroscience, Georgetown University School of Medicine, 3970 Reservoir Road, Washington, 20007, DC, USA Matthew Amontree, James O’Leary, Pauline Wonnenberg, Matthew Nelson & Katherine Conant Georgetown University School of Medicine, Interdisciplinary Program in Neuroscience, 3970 Reservoir Road, Washington, 20007, DC, USA Matthew Amontree, Pauline Wonnenberg, Matthew Nelson & Katherine Conant The authors declare no competing interests.

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