Oral 4-methylumbelliferone remodels brain extracellular matrix and improves memory in aged mice
The compound reduced perineuronal nets, dampened glial activation, and cut immune cell infiltration while restoring recognition memory.
Glia · Cimpean A et al. · Paper published 1 Oct 2026
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.
Why it matters
Targeting extracellular matrix components offers a potential way to lower chronic neuroinflammation and restore synaptic plasticity in the aging brain.
Caveats
The findings are limited to mice, and it remains unknown whether these effects translate to humans. The abstract also does not report sample sizes or the exact treatment duration.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
4-Methylumbelliferone Restores Age-Related Changes in Perineuronal Nets, Memory, and Neuroinflammation
Cimpean A, Mizerakova J, Martinez-Varea N et al.
Glia · 1 Oct 2026 · Peer-reviewed
- Relevance
- Core geroscience
- News value
- Notable
- Evidence
- Animals
- Status
- Peer-reviewed
More on Brain aging
See allHuman neurons accumulate far more mutations over lifespan than shorter-lived mammals
Cortical neurons gain mutations at similar yearly rates across six species, leaving aged humans with uniquely high mutational burdens and transcriptomic dysregulation.
bioRxiv : the preprint server for biology · Caglayan E et al.
CAR T cells targeting inflammatory bone marrow progenitors restore cognition in aged mice
Clearing these peripheral myeloid cells remodeled brain macrophages and improved cognitive performance without requiring the engineered immune cells to enter the brain.
bioRxiv · Harris AS et al.
Extracellular cGAMP drives neuroinflammation and premature aging phenotypes in mice
Loss of the cGAMP-degrading enzyme ENPP1 allows microglia-derived signaling molecules to trigger STING-dependent inflammation across multiple brain cell types.
bioRxiv · R. Carvalho D et al.
Directly converted human neuronal spheroids preserve donor age and model Alzheimer disease
The three-dimensional cell platform maintains biological aging markers while spontaneously developing hallmark pathologies of sporadic Alzheimer disease.
bioRxiv · Alsolami S et al.
Auditory nerve myelin degeneration defines a subtype of age-related hearing loss
Researchers linked poor auditory nerve synchrony and myelin degradation to amplified communication difficulties in older humans, beyond standard hearing thresholds.
medRxiv : the preprint server for health sciences · Harris KC et al.