Inhaled Xenon for AD?

Could inhaling xenon gas help fight Alzheimer’s disease? In the January 15 Science Translational Medicine, scientists led by Oleg Butovsky at Brigham and Women’s Hospital, Boston, and David Holtzman at Washington University in St. Louis, suggest that it could. Strange as it may sound, in mouse models of amyloidosis and tauopathy, huffing xenon lowered plaques and ameliorated neurodegeneration. How did the gas do this? By fine-tuning microglial activation to suppress pro-inflammatory cytokines and boost phagocytosis, according to the authors. These microglial changes depended on interferon-γ released by peripheral T cells that entered the brain.

  • Inhaled xenon shifts microglia from a pro-inflammatory to a phagocytic state.
  • Interferon-γ released by peripheral T cells flips the switch.
  • In mice, xenon curbed plaques and dystrophic neurites.
  • A Phase 1 trial in healthy elderly volunteers is starting.

Butovsky believes xenon has potential as an AD treatment. A Phase 1 clinical trial of xenon at BWH is recruiting healthy elderly volunteers to test safety and effects on immune cells. “I hope this paper will serve as a basis to open up new avenues of investigation,” Butovsky told Alzforum.

Other scientists were enthusiastic. “Overall, the study represents an advance in embracing the complexity of microglia signaling,” Jessica Rexach at the University of California, Los Angeles, wrote to Alzforum. Jonathan Kipnis at WashU called the findings striking (comments below).

Breath of Fresh Air? In the cortices of amyloidosis mice (left), microglia (green) surround dystrophic neurites (red) and amyloid plaques (white). In mice treated with weekly 40-minute doses of xenon for two months (right), these pathologies are reduced. [Courtesy of Brandao et al., Science Translational Medicine/AAAS.]

A noble gas, xenon is chemically inert. Despite this, it has a long history of use as an anesthetic. More recently, scientists have explored its potential as a neuroprotectant, showing that it preserves neurons after hypoxia or traumatic brain injury (Homi et al., 2003; Dingley et al., 2006; Campos-Pires et al., 2019). In cell culture studies, Patrick Michel and colleagues at the Paris Brain Institute shed light on the mechanism, finding that xenon quiets NMDA receptors, dampening excitotoxicity (Lavaur et al., 2016; Lavaur et al., 2017; Le Nogue et al., 2020). Along the same lines, another group reported that xenon protected neurons in hippocampal slices from the synaptotoxic effects of Aβ42 (Shi et al., 2023).

These studies led the authors to investigate whether xenon could ameliorate Alzheimer’s disease. Because Butovsky’s lab studies microglia, which carry most of the genetic risk for AD, they looked to these cells first. Joint first authors Wesley Brandao and Zhuoran Yin at BWH and Nimansha Jain at WashU put 3-month-old APP/PS1 mice into a chamber suffused with 30 percent xenon gas for 40 minutes (image below). Oxygen was maintained at 21 percent, the same as room air. Three, seven, or 14 days later, they isolated microglia and analyzed their gene expression by RNA-Seq.

Xenon Chamber. Three-month-old APP/PS1 mice were exposed to a single 40-minute dose of xenon gas in a sealed chamber, with microglia analyzed three, seven, or 14 days later. [Courtesy of Brandao et al., Science Translational Medicine/AAAS.]

Compared with microglia from untreated mice, those from animals exposed to the xenon dialed down expression of pro-inflammatory cytokines, while turning up genes related to interferon signaling and phagocytosis. These changes peaked at seven days after treatment. Interferon-expressing microglia have been found to have a beneficial, anti-inflammatory effect (Mar 2023 news).

Previously, Butovsky identified a microglial neurodegenerative phenotype (MGnD) associated with amyloid plaques in mouse models of amyloidosis, similar to the disease-associated microglia state described by others (Sep 2017 news; Jun 2017 news). Microglia isolated from xenon-treated mice expressed a mix of homeostatic and MGnD genes, indicating they had assumed a state intermediate between the two. This expression profile resembled a “pre-MGnD” state that Butovsky and colleagues recently described, which compacted plaques, protected synapses, and improved cognition in mice (Yin et al., 2024).

In keeping with this, in APP/PS1 mice treated with 40 minutes of xenon weekly from 2 to 4 months of age, plagues were 20 percent smaller and dystrophic neurites 30 percent smaller than in controls (image at top). In addition, their microglia expressed more antigen-presenting and synaptogenesis genes than did those from untreated mice.

Mouse and human microglia are quite different, however (May 2019 news; Jan 2020 news). Would these findings apply to human cells? To test this, the authors used chimeric mice developed in the lab of co-author Mathew Blurton-Jones. These have human microglia implanted into a 5xFAD background (Aug 2019 news). Again, after two months of weekly xenon treatment, plaque area and number of dystrophic neurite were about two-thirds of those in untreated mice. When microglia were ablated, xenon had no effect on plaques and neurites.

How does the xenon work? The authors found no change in glutamate receptors, ruling out an effect on NMDA receptors. Instead, xenon’s benefits depended on IFN-γ, as blocking this cytokine abolished them. Since T cells are known to produce IFN-γ, and T cells infiltrate the brain in APP/PS1, the authors investigated whether these cells could be the source. Sure enough, xenon induced IFN-γ expression in isolated T cells. The same thing happened in mice exposed to xenon, with T cell activation peaking at three days after xenon treatment, before the peak of microglial change.

Other scientists said these findings dovetail with their work. Kipnis has shown that IFN-γ from T cells modulates microglia and protects the brain after injury (Gao et al., 2024). Rexach recently reported extensive interactions between T cells and microglia in AD (Yamakawa and Rexach, 2024).

Tau Too?
Amyloidosis mouse models do not develop much tau pathology. To examine xenon’s effects on tangles, the authors turned to P301S mice carrying human APOE4. These mice, engineered in Holtzman’s lab, develop aggressive pathology (Sep 2017 news). Nonetheless, weekly xenon treatments from 6 to 9 months of age slowed neurodegeneration, with treated mice having slightly bigger hippocampi than untreated ones.

As in amyloidosis models, xenon shifted microglia in these tauopathy mice from a pro-inflammatory to a phagocytic state. However, the microglia expression profiles in xenon-treated amyloidosis versus tauopathy models were distinct, with only about 20 percent of their genes changing in common. Notably, in both models, microglia suppressed APOE and TREM2, genes crucial for the induction of the classic MGnD or DAM states. In future work, Butovsky will examine xenon’s effects on models of amyotrophic lateral sclerosis, multiple sclerosis, and age-related macular degeneration.

Michel at the Paris Brain Institute believes the data have clinical implications. “These findings open potential therapeutic avenues, as the inflammatory response of microglia is believed to play a critical role in the progression of Alzheimer’s disease,” he wrote to Alzforum (comment below).

The Phase 1 trial at BWH is led by Howard Weiner there, and will enroll healthy people older than 65. They will receive a single dose of xenon for either 10, 20, 30, or 40 minutes. Researchers will collect blood to analyze effects on peripheral T cells, which may help determine the pharmacokinetic and pharmacodynamic properties of the gas. If safe, the trial will go on to test multiple doses.

Xenon is also being tested in clinical trials for anxiety and depression (Dobrovolsky et al., 2017).—Madolyn Bowman Rogers

Comments

  1. This is an interesting paper that explores the impact of xenon therapy on microglia trajectories in different transgenic models with different disease-associated pathologies. The results indicate beneficial effects of xenon treatment on disease across varied pathological contexts. This included shifts in microglia away from certain types of disease responses, and toward others.

    In the APP/PSEN1 models, xenon treatment increased the microglial interferon response while also driving beneficial outcomes with respect to amyloid pathology and neuritic plaque density. Accompanying this were changes in CD8 T cells and interferon gamma signaling, suggesting these processes may participate in beneficial effects in the context of dysregulated amyloid processing. Interestingly, this corresponds with findings from our recent unbiased human work indicating the greatest number of interactions gained in disease occur between CD8 T cells and amyloid-responsive microglia (Yamakawa and Rexach, 2024). Moreover, these observations support extensive cross talk between microglia states early in disease, consistent with prior work (Rexach et al., 2021; and others). One outstanding question is if synaptic density changed in this model, because prior work showed that microglia interferon signaling correlated with increased complement-mediated synaptic clearance (Lall et al., 2021). 

    In the APOE4 and MAPT mutation model, they report improved synaptic density, changes in the pattern of tau deposition, and decreased hippocampal degeneration. Therefore, xenon had highly context-specific effects of microglia signaling on disease but was consistently beneficial.

    It will be important to determine the mechanism to translate this further. The gene-expression data showing consistent changes in lipid signaling warrants further investigation as a potential mechanism. This is eye-catching, given known roles for lipid signaling in governing microglia and macrophage inflammation.

    Overall, the study represents an advance in embracing the complexity of microglia signaling for functional validation studies.

    References:

    Yamakawa M, Rexach JE. Cell States and Interactions of CD8 T Cells and Disease-Enriched Microglia in Human Brains with Alzheimer's Disease. Biomedicines. 2024 Jan 29;12(2) PubMed.

    Rexach JE, Polioudakis D, Yin A, Swarup V, Chang TS, Nguyen T, Sarkar A, Chen L, Huang J, Lin LC, Seeley W, Trojanowski JQ, Malhotra D, Geschwind DH. Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression. Cell Rep. 2020 Nov 17;33(7):108398. PubMed.

    Lall D, Lorenzini I, Mota TA, Bell S, Mahan TE, Ulrich JD, Davtyan H, Rexach JE, Muhammad AK, Shelest O, Landeros J, Vazquez M, Kim J, Ghaffari L, O'Rourke JG, Geschwind DH, Blurton-Jones M, Holtzman DM, Sattler R, Baloh RH. C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron. 2021 Jul 21;109(14):2275-2291.e8. Epub 2021 Jun 15 PubMed.

    View all comments by Jessica Rexach
    • User Profile Image Jonathan Kipnis
      Washington University in St. Louis, School of Medicine
    • Posted:

    This is a very interesting story, and the results are striking. The microglia phenotype is super interesting and the fact that it is mediated by IFN-γ producing T cells is fascinating. We have recently published a paper where we showed T cell-derived IFN-γ to be beneficial after CNS injury, also through modulation of microglia and macrophage phenotype in the injured CNS (Gao et al., 2024).

    I do not think we, as a field, completely understand how IFN-γ drives protective responses in CNS myeloid cells under acute and chronic neurodegenerative conditions, but empirically the data here are very strong and the underlying molecular mechanism should be further investigated.

    References:

    Gao W, Kim MW, Dykstra T, Du S, Boskovic P, Lichti CF, Ruiz-Cardozo MA, Gu X, Weizman Shapira T, Rustenhoven J, Molina C, Smirnov I, Merbl Y, Ray WZ, Kipnis J. Engineered T cell therapy for central nervous system injury. Nature. 2024 Oct;634(8034):693-701. Epub 2024 Sep 4 PubMed.

    View all comments by Jonathan Kipnis

  3. Despite being chemically inert, the noble gas Xenon (Xe) has demonstrated intriguing biological properties that have potential clinical applications. Xe gas possesses anesthetic and antidepressant effects, and shows promise as a neuroprotectant in both acute and progressive neurodegenerative conditions (Winkler et al., 2016; Lavaur et al., 2016). These benefits are primarily attributed to a reduction in NMDA receptor-mediated synaptic neurotransmission (Banks et al., 2010). In this paper a team of scientists led by Oleg Butovsky and David Holtzman demonstrates that Xe inhalation in subanesthetic doses may slow the progression of Alzheimer’s disease pathology in several mouse models that replicate some of the key features of this disorder, specifically amyloid deposition, tau aggregation and dysregulation of the brain immune system.

    Their research indicates that Xe treatment primarily operates by reducing brain inflammatory responses mediated by microglial cells. Specifically, Xe inhalation seems to facilitate the transition of neurodegenerative microglia toward an intermediate activation state, which helps limit amyloid plaque deposition and reduces dystrophic neurites in amyloidogenic mouse models (APP/PS1; 5xFAD). Additionally, Xe suppresses brain atrophy, and reduces proinflammatory microglial responses in the P301S-APOE4 mouse model of tauopathy.

    The researchers suggest that interferon-γ coming from T cells infiltrating into the brain may play a key role in the modulatory effects of Xe on microglia. These findings open potential therapeutic avenues, as the inflammatory response of microglia is believed to play a critical role in the progression of Alzheimer’s disease.

    References:

    Winkler DA, Thornton A, Farjot G, Katz I. The diverse biological properties of the chemically inert noble gases. Pharmacol Ther. 2016 Apr;160:44-64. Epub 2016 Feb 16 PubMed.

    Lavaur J, Lemaire M, Pype J, Le Nogue D, Hirsch EC, Michel PP. Neuroprotective and neurorestorative potential of xenon. Cell Death Dis. 2016 Apr 7;7(4):e2182. PubMed.

    Banks P, Franks NP, Dickinson R. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia. Anesthesiology. 2010 Mar;112(3):614-22. PubMed.

    View all comments by Patrick Pierre Michel

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References

Research Models Citations

  1. APPPS1
  2. 5xFAD (B6SJL)

News Citations

  1. Alzheimer’s Gene MS4A4A Governs the State of Microglia
  2. ApoE and Trem2 Flip a Microglial Switch in Neurodegenerative Disease
  3. Hot DAM: Specific Microglia Engulf Plaques
  4. When It Comes to Alzheimer’s Disease, Do Human Microglia Even Give a DAM?
  5. Human and Mouse Microglia React Differently to Amyloid
  6. Human Microglia Make Themselves at Home in Mouse Brain
  7. ApoE4 Makes All Things Tau Worse, From Beginning to End

Mutations Citations

  1. MAPT P301S

Paper Citations

  1. Homi HM, Yokoo N, Ma D, Warner DS, Franks NP, Maze M, Grocott HP. The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice. Anesthesiology. 2003 Oct;99(4):876-81. PubMed.
  2. Dingley J, Tooley J, Porter H, Thoresen M. Xenon provides short-term neuroprotection in neonatal rats when administered after hypoxia-ischemia. Stroke. 2006 Feb;37(2):501-6. Epub 2005 Dec 22 PubMed.
  3. Campos-Pires R, Hirnet T, Valeo F, Ong BE, Radyushkin K, Aldhoun J, Saville J, Edge CJ, Franks NP, Thal SC, Dickinson R. Xenon improves long-term cognitive function, reduces neuronal loss and chronic neuroinflammation, and improves survival after traumatic brain injury in mice. Br J Anaesth. 2019 Jul;123(1):60-73. Epub 2019 May 21 PubMed.
  4. Lavaur J, Lemaire M, Pype J, Nogue DL, Hirsch EC, Michel PP. Xenon-mediated neuroprotection in response to sustained, low-level excitotoxic stress. Cell Death Discov. 2016;2:16018. Epub 2016 May 16 PubMed.
  5. Lavaur J, Le Nogue D, Lemaire M, Pype J, Farjot G, Hirsch EC, Michel PP. The noble gas xenon provides protection and trophic stimulation to midbrain dopamine neurons. J Neurochem. 2017 Jul;142(1):14-28. Epub 2017 May 16 PubMed.
  6. Le Nogue D, Lavaur J, Milet A, Ramirez-Gil JF, Katz I, Lemaire M, Farjot G, Hirsch EC, Michel PP. Neuroprotection of dopamine neurons by xenon against low-level excitotoxic insults is not reproduced by other noble gases. J Neural Transm (Vienna). 2020 Jan;127(1):27-34. Epub 2019 Dec 5 PubMed.
  7. Shi D, Wong JK, Zhu K, Noakes PG, Rammes G. The Anaesthetics Isoflurane and Xenon Reverse the Synaptotoxic Effects of Aβ1-42 on Megf10-Dependent Astrocytic Synapse Elimination and Spine Density in Ex Vivo Hippocampal Brain Slices. Int J Mol Sci. 2023 Jan 4;24(2) PubMed.
  8. Yin Z, Herron S, Silveira S, Kleemann K, Gauthier C, Mallah D, Cheng Y, Margeta MA, Pitts KM, Barry JL, Subramanian A, Shorey H, Brandao W, Durao A, Delpech JC, Madore C, Jedrychowski M, Ajay AK, Murugaiyan G, Hersh SW, Ikezu S, Ikezu T, Butovsky O. Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease. Nat Neurosci. 2023 Jul;26(7):1196-1207. Epub 2023 Jun 8 PubMed.
  9. Gao W, Kim MW, Dykstra T, Du S, Boskovic P, Lichti CF, Ruiz-Cardozo MA, Gu X, Weizman Shapira T, Rustenhoven J, Molina C, Smirnov I, Merbl Y, Ray WZ, Kipnis J. Engineered T cell therapy for central nervous system injury. Nature. 2024 Oct;634(8034):693-701. Epub 2024 Sep 4 PubMed.
  10. Yamakawa M, Rexach JE. Cell States and Interactions of CD8 T Cells and Disease-Enriched Microglia in Human Brains with Alzheimer's Disease. Biomedicines. 2024 Jan 29;12(2) PubMed.
  11. Dobrovolsky A, Ichim TE, Ma D, Kesari S, Bogin V. Xenon in the treatment of panic disorder: an open label study. J Transl Med. 2017 Jun 13;15(1):137. PubMed.

Further Reading

Primary Papers

  1. Brandao W, Jain N, Yin Z, Kleemann KL, Carpenter M, Bao X, Serrano JR, Tycksen E, Durao A, Barry JL, Baufeld C, Guneykaya D, Zhang X, Litvinchuk A, Jiang H, Rosenzweig N, Pitts KM, Aronchik M, Yahya T, Cao T, Takahashi MK, Krishnan R, Davtyan H, Ulrich JD, Blurton-Jones M, Ilin I, Weiner HL, Holtzman DM, Butovsky O. Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy. Sci Transl Med. 2025 Jan 15;17(781):eadk3690. Epub 2025 Jan 15 PubMed.

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