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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University of California, Los Angeles
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 RexachWashington University in St. Louis, School of Medicine
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 KipnisParis Brain Institute
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 MichelThis is a very interesting and unique study from leaders in the field.
While Xe has been previously used as a general anesthetic and its benefits studied in models of brain injury, its potential effect on AD, and its modulation of microglial activation, were never investigated. Here, the authors fill this gap. They provide convincing data that Xe can reduce microglial activation and promote a protective microglial program.
The most surprising findings were that IFNγ signaling was essential for mediating the effects of Xe on microglia, and that Xe inhalation increases IFNγ production by CD8 T cells. This highlights the complex function of IFNγ, which can also exert anti-inflammatory effects, but leaves us with unanswered questions: How does Xe mediate such IFNγ production? And what are the molecular targets involved?
View all comments by Florent GinhouxWeizmann Institute of Science
This paper is intriguing as it proposes xenon inhalation as a potential treatment for Alzheimer’s disease. While xenon is widely used in medicine for various short-term procedures, the authors suggest that Xe inhalation could alleviate Alzheimer’s symptoms by elegantly proposing a mechanism of action that links the peripheral immune system, specifically the effects of T-cell-derived IFN-γ, to microglial fate.
Although the results highlight key factors that link disease progression with local brain inflammation, particularly the role of microglia and T cells, further studies are needed to investigate the diversity of microglia under these conditions, the fate of monocyte-derived macrophages, and the functional aspects of these interactions. Additionally, safety concerns must be addressed to validate these findings.
View all comments by Michal SchwartzBrigham and Women's Hospital/Harvard Medical School
The findings on Xenon-mediated induction of IFN-γ-producing T cells in the periphery and their role in modulating the pre-MGnD beneficial state in AD mouse models are intriguing. These results align with our previous work on the protective microglial state mediated by miR-155 and interferon-γ signaling in an Alzheimer's disease mouse model (Yin et al., 2023). Furthermore, they support previous studies from the laboratories of Michal Schwartz (Baruch et al., 2015; Baruch et al., 2016; Butovsky et al., 2006; Kunis et al., 2013), Jonathan Kipnis (Gao et al., 2024; Filiano et al., 2016), Alon Monsonego (Monsonego et al., 2006), and Rudolph Tanzi (Yang et al., 2021), among others (with apologies for not citing all contributors), highlighting the beneficial role of IFN-γ signaling in neurodegeneration.
However, this regulation must be finely controlled to maintain peripheral immune homeostasis while still enabling the necessary immune response to reach the brain and induce beneficial IFN-γ-mediated MGnD microglia.
This study also introduced a novel transgenic Clec7a-CREERT mouse model, which allows for the specific depletion of the MGnD subset. This provides direct evidence that MGnD microglia exert beneficial effects in AD mouse models.
The ultimate validation of these findings will come from the upcoming Phase 1 clinical trial, where it will be critical to assess whether Xenon induces similar immune regulatory effects, including IFN-γ signaling, in humans: “Study Finding Xenon Gas Could Protect Against Alzheimer’s Disease Leads to Start of Clinical Trial.”
References:
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.
Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015 Aug 18;6:7967. PubMed.
Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, Kertser A, David E, Amit I, Schwartz M. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.
Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006 Jan;31(1):149-60. Epub 2005 Nov 16 PubMed.
Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, Schwartz M. IFN-γ-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain. 2013 Nov;136(Pt 11):3427-40. Epub 2013 Oct 1 PubMed.
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.
Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, Gadani SP, Turner SD, Weng Z, Peerzade SN, Chen H, Lee KS, Scott MM, Beenhakker MP, Litvak V, Kipnis J. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016 Jul 21;535(7612):425-9. Epub 2016 Jul 13 PubMed.
Monsonego A, Imitola J, Petrovic S, Zota V, Nemirovsky A, Baron R, Fisher Y, Owens T, Weiner HL. Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5048-53. PubMed.
Yang HS, Zhang C, Carlyle BC, Zhen SY, Trombetta BA, Schultz AP, Pruzin JJ, Fitzpatrick CD, Yau WW, Kirn DR, Rentz DM, Arnold SE, Johnson KA, Sperling RA, Chhatwal JP, Tanzi RE. Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults. Alzheimers Dement. 2021 Jun 23; PubMed.
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