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bioRxiv · 10.64898/2026.05.21.726929

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

Amontree, M.·O'Leary, J.·Wonnenberg, P.·Nelson, M.·Conant, K.
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Abstract

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 Alzheimers 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 Alzheimers 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 A{beta}1-42/A{beta}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.

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Amontree, M., O'Leary, J., Wonnenberg, P., Nelson, M., Conant, K.. 2026-05-25. 4-methylumbelliferone attenuates amyloid pathology and learning deficits in the APP/PS1 mouse model. https://doi.org/10.64898/2026.05.21.726929

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