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By Unleashing Microglial cGAS, Tau STINGs Neurons

Series - International Conference on Alzheimer's and Parkinson's Diseases 2023:

Springing a leak is rarely good news, but when microglial mitochondria start oozing, it can be particularly bad in situations of tauopathy. So conclude scientists led by Li Gan and Sadaf Amin, Weill Cornell Medicine, New York, in the April 24 Nature Neuroscience.

  • Tau fibrils damage microglial mitochondria.
  • Leaked mtDNA triggers cGAS and STING, drivers of interferon pathways.
  • IFN suppresses neuronal genes, weakening resistance to tau pathology.

The authors report that when mitochondrial DNA drips into the cytosol, it sets off a series of reactions that unleashes an interferon response. That, in turn, douses expression of neuronal genes that protect against tau pathology. Neutralizing the mtDNA threat rescued learning and memory in mouse models of tauopathy. The findings are the latest in a string of reports linking neurodegeneration to wayward nucleic acids, be they double-stranded RNA or DNA. Gan first reported on this work at AD/PD 2022 in Barcelona, and expanded on the data at the 2023 meeting, held in Gothenburg, Sweden, March 28 to April 1.

“There is a lot to be excited about here,” wrote Russell Swerdlow, Kansas University Medical Center (comment below). “If tau indeed messes with mitochondria, and induces a mitochondria DNA leak into the cytoplasm that triggers microglial activation via the cGAS-Sting pathway, that could have important implications for the basis of AD brain inflammation.”

A “Gascade?” Foreign DNA that enters the cytosol activates cGAS, setting off inflammation via activation of STING and phosphorylation of interferon regulatory factor 3. IRF3 drives transcription of interferons in the nucleus. By letting DNA out of mitochondria, pathogenic tau drives the same “gascade.” [Image courtesy Ding et al., 2022, Frontiers in Molecular Neuroscience.] 

In a prior study of tau protein interaction networks, Gan and her team were surprised to discover that the wild-type microtubule binding protein cozies up to mitochondrial partners, and that tau carrying a pathogenic mutation rendered the mini power plants much less efficient (Jan 2022 news).

As Gan described in Barcelona last year, Amin then extended the work to microglia. She found that fibrils of tau spark an interferon response cascade in these innate immune cells that is typically driven by viral RNA or DNA (see model above). Amin found that the fibrils of tau somehow damaged the microglial mitochondria, causing them to leak their DNA into the cytosol, activating cyclic GMP-AMP synthase (cGAS), which in turn sets off STING, aka stimulator of interferon genes. By knocking out cGAS or dosing mice with the cGAS inhibitor TDI-6570, Amin was able to dampen the interferon response and preserve synapses and memory loss in P301S tau mice (see image below and Apr 2022 conference news).

However, cGAS suppression did not affect tau pathology. How, then, did it protect neurons?

With, or Without, cGAS? In wild-type hippocampal fields (left panels), knocking out cGAS (bottom) has no effect on levels of the postsynaptic marker PSD-95 (red). In P301S mice (right panel), PSD95 drops (top), but cGAS knockout restores it (bottom). [Courtesy of Udeochu et al., Nature Neuroscience 2023.]

Gan addressed this in Gothenburg. Co-first authors Amin, Joe Udeochu, and Yige Huang found that if they deleted cGAS, neurons up- and downregulated a plethora of genes. Among them, myocyte enhancer factor 2c stood out as being highly expressed among inhibitory and excitatory neurons. Mef2 is a family of transcription factors that are induced by neuronal activity, and they modulate synaptic density (Flavell et al., 2006). Genetic variants near the Mef2c locus have been linked to Alzheimer’s disease, and previously, researchers led by Li Huei Tsai at MIT reported that the gene confers resilience to neurons in mouse models of tauopathy (Mar 2019 news; Barker et al., 2021). Gan’s findings fit with that work, indicating that the cGAS pathway suppresses Mef2c function. Tsai is a co-author on the paper.

To test this idea more directly, the authors injected mice five times over 12 days with 5,6 dimethylxanthenone-4-acetic acid, a STING agonist, to chronically induce IFN-I responses. In wild-type mice, but not in mice lacking IFN receptors, the treatment suppressed Mef2c.

Beefing up Mef2c. In the CA1 hippocampal layer in P301S tau mice (top), neurons (green) express little Mef2c (red). When cGAS is knocked out (bottom), Mef2c expression jumps about 40 percent. [Courtesy of Udeochu et al., Nature Neuroscience, 2023.]

What about genes downstream of Mef2c? The transcription factor regulates 400+ genes. Gloria Huang, a graduate student in the Gan lab, found that expression of more than half of those also change in P301S mice when cGAS is knocked out. Many of these are resilience genes identified by the prior work from the Tsai lab. Those same changes could be evoked by treating mice with the cGAS inhibitor TDI-6570.

All told, Gan believes that by preserving the expression of resilience genes, cGAS-STING inhibition could be protective not only in tauopathies, but in other neurodegenerative diseases as well. At AD/PD, Valina Dawson, Johns Hopkins University, Baltimore, noted in her talk that knocking out STING protects against dopaminergic neuron loss and motor deficits when α-synuclein fibrils are injected into mouse brain. She showed data suggesting that levels of the STING protein double in the substantia nigra in people with Parkinson’s compared to healthy controls (Hinkle et al., 2022). Familial PD mutations damage mitochondria and activate the cGAS/STING pathway, and TDP-43 does the same in ALS (Sliter et al., 2018; Yu et al., 2020). 

Furthermore, tau has been implicated in the production of double-stranded RNA in astrocytes, and to cause inflammation in this way, while knocking out cGAS appears to reduce plaque accumulation in mouse models of AD (Jan 2023 news). The cGAS/STING pathway might also help explain links between viral infections and a person’s risk for AD (see Part 10 of this AD/PD series).

cGAS knockout mice seem healthy. To Gan's mind, this implies that targeting this enzyme in multiple neurodegenerative diseases might be safe. “We would propose to continue to understand how cGAS/STING drives neurodegeneration as a common mechanism, most likely triggered, partially at least, by mitochondrial dysfunction,” said Gan.—Tom Fagan

Comments

  1. There is a lot here to be excited about, and Dr. Gan’s group should be commended for considering a role for tau-mitochondria interactions. Here, they add perspective to prior work that showed physical interactions occur, and these physical associations have functional consequences. If tau indeed messes with mitochondria, and induces a mitochondria DNA leak into the cytoplasm that triggers microglial activation via the cGAS-Sting pathway, that could have important implications for the basis of AD brain inflammation.

    I do think it is important to keep in mind that data generated by several groups also show a reverse relationship, in that mitochondria also mess with tau. Mitochondrial dysfunction increases neuronal cell tau expression, tau levels, phosphorylation, and splicing (Weidling et al., 2020). It is becoming increasingly clear that mitochondria interact with tau biology, as well as with APP, Aβ, and ApoE biology.

    References:

    Weidling IW, Wilkins HM, Koppel SJ, Hutfles L, Wang X, Kalani A, Menta BW, Ryan B, Perez-Ortiz J, Gamblin TC, Swerdlow RH. Mitochondrial DNA Manipulations Affect Tau Oligomerization. J Alzheimers Dis. 2020;77(1):149-163. PubMed.

    View all comments by Russell Swerdlow

  2. This is a very interesting and comprehensive piece of work diving into the mechanisms of microglial-induced neuronal toxicity in the context of tauopathy. It is in line with previous work by myself (Mancuso et al., 2019) and the Holtzman lab (Shi et al., 2017; Shi et al., 2019) that already reported a detrimental effect of microglia in mice carrying tau mutations.

    I find particularly interesting the finding that tau aggregates are able to induce mitochondrial damage in the microglia, and unleash their activation. As far as I know, this is the first time a mechanism as such is described.

    The second exciting observation is that Cgas deletion has a strong effect of neuronal genes related to resilience. In fact, looking carefully at the data, it appears that engagement of the Cgas pathways actually decreases the expression of resilience genes (when comparing P301S versus wild type mice). This may point to an interesting scenario where microglia are not actively inducing neuronal toxicity but, conversely, where they reduce the capacity of neurons to protect themselves against damage, therefore sensitizing the system to the development of dementia.

    This work also raises questions regarding the role of microglia linking amyloid and tau pathology. Is a scenario plausible where Aβ induces Cgas-IFN activation, leading to a diminished resilience of neurons to tau accumulation and resulting in neurodegeneration?

    References:

    Mancuso R, Fryatt G, Cleal M, Obst J, Pipi E, Monzón-Sandoval J, Ribe E, Winchester L, Webber C, Nevado A, Jacobs T, Austin N, Theunis C, Grauwen K, Daniela Ruiz E, Mudher A, Vicente-Rodriguez M, Parker CA, Simmons C, Cash D, Richardson J, NIMA Consortium, Jones DN, Lovestone S, Gómez-Nicola D, Perry VH. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain. 2019 Oct 1;142(10):3243-3264. PubMed.

    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.

    Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.

    View all comments by Renzo Mancuso

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References

News Citations

  1. Survey of Tau Partners Highlights Synaptic, Mitochondrial Roles
  2. Just Like Viruses, Tau Can Unleash Interferons
  3. Paper Alerts: Massive GWAS Studies Published
  4. Does Double-Stranded RNA From Jumping Genes Mediate Tau Toxicity?
  5. TREM2 Protects the Brain From Herpes. The Virus Fights Back.

Paper Citations

  1. Ding J, Dai Y, Zhu J, Fan X, Zhang H, Tang B. Research advances in cGAS-stimulator of interferon genes pathway and central nervous system diseases: Focus on new therapeutic approaches. Front Mol Neurosci. 2022;15:1050837. Epub 2022 Dec 22 PubMed.
  2. Flavell SW, Cowan CW, Kim TK, Greer PL, Lin Y, Paradis S, Griffith EC, Hu LS, Chen C, Greenberg ME. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science. 2006 Feb 17;311(5763):1008-12. PubMed.
  3. Barker SJ, Raju RM, Milman NE, Wang J, Davila-Velderrain J, Gunter-Rahman F, Parro CC, Bozzelli PL, Abdurrob F, Abdelaal K, Bennett DA, Kellis M, Tsai LH. MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration. Sci Transl Med. 2021 Nov 3;13(618):eabd7695. PubMed.
  4. Hinkle JT, Patel J, Panicker N, Karuppagounder SS, Biswas D, Belingon B, Chen R, Brahmachari S, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM. STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy. Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2118819119. Epub 2022 Apr 8 PubMed.
  5. Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ. Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018 Sep;561(7722):258-262. Epub 2018 Aug 22 PubMed.
  6. Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RR, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020 Oct 29;183(3):636-649.e18. Epub 2020 Oct 7 PubMed.

Further Reading

Papers

  1. Roy ER, Wang B, Wan YW, Chiu G, Cole A, Yin Z, Propson NE, Xu Y, Jankowsky JL, Liu Z, Lee VM, Trojanowski JQ, Ginsberg SD, Butovsky O, Zheng H, Cao W. Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J Clin Invest. 2020 Apr 1;130(4):1912-1930. PubMed.

Primary Papers

  1. Udeochu JC, Amin S, Huang Y, Fan L, Torres ER, Carling GK, Liu B, McGurran H, Coronas-Samano G, Kauwe G, Mousa GA, Wong MY, Ye P, Nagiri RK, Lo I, Holtzman J, Corona C, Yarahmady A, Gill MT, Raju RM, Mok SA, Gong S, Luo W, Zhao M, Tracy TE, Ratan RR, Tsai LH, Sinha SC, Gan L. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. Nat Neurosci. 2023 May;26(5):737-750. Epub 2023 Apr 24 PubMed.

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