Inhaled Xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy [Xenon PD in MGnD paradigm]

Alzheimer's disease (AD) is the most prevalent neurodegenerativedisorder. Currently, anti-amyloid antibody treatments modestly slow disease progression in milddementia due to AD.Emerging evidence shows that homeostatic dysregulation of the brainimmune system, especially that orchestrated by microglia, plays a significant role in the onset andprogression of the disease, including an increase in neuroinflammation and oxidative stress.Thus,a major question is how to modulate the phenotype and function of microglia to treat AD.Xenongas (Xe) is a noble gas used in human patients as an anesthetic and neuroprotectant in treatingbrain injuries. Xe penetratestheblood-brain barrier, which can make it an effective therapeutic.WeidentifiedthatXeinhalationpolarizesmouse and human microglia towards an intermediatestate of activation that we have termedas'pre-MGnD' in anacute neurodegeneration model andmouse models with AD-like pathology, i.e.,5xFAD (amyloid) and P301S (tau). This microglialphenotypic transition enhanced amyloid plaque compaction and reduced dystrophic neurites.Moreover, Xe inhalation reduced brain atrophy neuroinflammationand improved nest-buildingbehavior in APOE4:P301S mice. Mechanistically, Xe inhalation polarizes homeostatic microgliatoward a pre-MGnD state via IFN?signaling that maintains the microglial phagocytic responsewhile suppressing its pro-inflammatory properties. These resultssupport the translation of Xeinhalation as a novel approach to treatingAD. Overall design: C57BL/6 (WT) mice receive injection of apoptotic neurons in cortex and hippocampus. Two hours after the injection of apoptotic neurons, the mice were treated with Xe at four different concentrations, starting with 6%, 12%, 30%, and 35% for 40 minutes and euthanized 14 hours later. Microglia were isolated to RNAseq analysis.