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Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre\u2013neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP\/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP\/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-\u03b3 signaling that maintained the microglial phagocytic response in APP\/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.<\/jats:p>","DOI":"10.1126\/scitranslmed.adk3690","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T18:58:19Z","timestamp":1736967499000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy"],"prefix":"10.1126","volume":"17","author":[{"given":"Wesley","family":"Brandao","sequence":"first","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5360-5466","authenticated-orcid":true,"given":"Nimansha","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. 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