{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:54:31Z","timestamp":1790769271662,"version":"4.1.0"},"reference-count":69,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["(GACR) 23\u201005540S"],"award-info":[{"award-number":["(GACR) 23\u201005540S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Aging\u2010associated cognitive decline is closely linked to dysregulated glial activity and chronic neuroinflammation, which together constrain neuronal plasticity. Astrocytes and microglia are key regulators of the brain extracellular matrix (ECM), including perineuronal nets (PNNs), whose accumulation during aging contributes to reduced synaptic flexibility. Targeting ECM\u2013glia interactions therefore represents a promising strategy to modulate neuroinflammatory and plasticity\u2010related processes. Here, we investigated the effects of long\u2010term oral administration of 4\u2010methylumbelliferone (4\u2010MU), an inhibitor of hyaluronan and chondroitin sulfate synthesis, on glial reactivity, ECM remodeling, and cognitive function in aged mice (20\u201322\u2009months). Aging was associated with PNN remodeling alongside pronounced astrocytic and microglial activation and infiltration of peripheral immune cells. Chronic 4\u2010MU treatment reduced PNN accumulation to levels observed in younger (10\u2010month\u2010old) mice, indicating effective ECM remodeling. Notably, this was accompanied by a marked attenuation of astrocyte and microglial activation and a reduction in immune cell infiltration, suggesting a broad normalization of the neuroinflammatory milieu. Functionally, these glia\u2010associated changes were paralleled by improved recognition memory, with treated aged mice performing at or above the level of younger controls. Long\u2010term 4\u2010MU administration was well tolerated, with no evident adverse effects. Together, our findings identify ECM modulation as a mechanism to regulate glial reactivity and neuroimmune interactions in the aging brain. By targeting hyaluronan\u2010dependent pathways, 4\u2010MU links ECM remodeling to suppression of neuroinflammation and restoration of cognitive function, highlighting its therapeutic potential in age\u2010related neurodegenerative processes.<\/jats:p>","DOI":"10.1002\/glia.70233","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:55:54Z","timestamp":1790765754000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["4\u2010Methylumbelliferone Restores Age\u2010Related Changes in Perineuronal Nets, Memory, and Neuroinflammation"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3550-2441","authenticated-orcid":false,"given":"Anda","family":"Cimpean","sequence":"first","affiliation":[{"name":"Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4702-3350","authenticated-orcid":false,"given":"Jana","family":"Mizerakova","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0775-1734","authenticated-orcid":false,"given":"Noelia","family":"Martinez\u2010Varea","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Marekova","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7622-5837","authenticated-orcid":false,"given":"Lucia","family":"Machova Urdzikova","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7990-4568","authenticated-orcid":false,"given":"James W.","family":"Fawcett","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences  Prague Czech Republic"},{"name":"Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4644-9212","authenticated-orcid":false,"given":"Pavla","family":"Jendelova","sequence":"additional","affiliation":[{"name":"Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9798-9083","authenticated-orcid":false,"given":"Jessica C. 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