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

Authors
Anda Cimpean, Jana Dubisova, Noelia Martinez-Varea, Lucia Urdzikova-Machova, James W. Fawcett, Pavla Jendelova, Jessica C.F. Kwok


Lab
Babraham Institute; Johns Hopkins University; Morgridge Institute; Northeastern University; Rutgers University; Tel Aviv University; The Sainsbury Laboratory; Berkeley; San Diego; Vanderbilt University; Yale University

Journal
bioRxiv

Abstract

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

Keywords/Topics
young rodents; long-term oral 4-mu administration; aged mice; 22-month-old mice; peripheral immune cell infiltration; chronic 4-mu administration; -methylumbelliferone; age-related changes; perineuronal nets; memory

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.biorxiv.org/content/10.64898/2026.01.30.702721.abstract

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