Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.

Brandao, Wesley; Jain, Nimansha; Yin, Zhuoran; Kleemann, Kilian L.; Carpenter, Madison; Bao, Xin; Serrano, Javier R.; Tycksen, Eric; Durao, Ana; Barry, Jen-Li; Baufeld, Caroline; Guneykaya, Dilansu; Zhang, Xiaoming; Litvinchuk, Alexandra; Jiang, Hong; Rosenzweig, Neta; Pitts, Kristen M.; Aronchik, Michael; Yahya, Taha; Cao, Tian

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. 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–neurodegenerative 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-γ 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. Editor's summary: Aberrant regulation of microglia is known to contribute to Alzheimer's disease (AD). Brandao et al. now report that xenon (Xe) gas inhalation promotes a protective microglial response in mouse models of AD. Xe inhalation induced microglial phagocytosis and reduced amyloidosis, neuritic dystrophy, and inflammation while promoting a protective microglial phenotype. It also enhanced IFN-γ signaling, suppressed inflammation, and alleviated brain atrophy in mice with tauopathy. In the 5xFAD mouse model of AD, Xe modulated CD8 T cells, boosting IFN-γ production, whereas IFN-γ blockade impaired this effect. These findings suggest that Xe inhalation may be a therapeutic strategy for modulating microglial activity and reducing neurodegeneration in AD. —Orla Smith

ALZHEIMER'S disease; PHENOTYPIC plasticity; CEREBRAL atrophy; AMYLOID plaque; NOBLE gases

Science Translational Medicine, 2025, Vol 17, Issue 781, p1

1946-6234

Academic Journal

10.1126/scitranslmed.adk3690