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Cited by 104Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Blockade of STING Activation Alleviates Microglial Dysfunction and a Broad Spectrum of Alzheimer's Disease Pathologies

Open access
Chung, Sunwoo, Jeong, June-Hyun, Park, Jong-Chan, Han, Jong Won, Lee, Yeajina, Kim, Jong-Il, Mook-Jung, Inhee·2024·Experimental & Molecular Medicine
DOI 10.1038/s12276-024-01295-yPMC PMC11447230
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Abstract

Abnormal glial activation promotes neurodegeneration in Alzheimer’s disease (AD), the most common cause of dementia. Stimulation of the cGAS-STING pathway induces microglial dysfunction and sterile inflammation, which exacerbates AD. We showed that inhibiting STING activation can control microglia and ameliorate a wide spectrum of AD symptoms. The cGAS-STING pathway is required for the detection of ectopic DNA and the subsequent immune response. Amyloid-β (Aβ) and tau induce mitochondrial stress, which causes DNA to be released into the cytoplasm of microglia. cGAS and STING are highly expressed in Aβ plaque-associated microglia, and neuronal STING is upregulated in the brains of AD model animals. The presence of the APOE ε4 allele, an AD risk factor, also upregulated both proteins. STING activation was necessary for microglial NLRP3 activation, proinflammatory responses, and type-I-interferon responses. Pharmacological STING inhibition reduced a wide range of AD pathogenic features in App NL-G-F /hTau double-knock-in mice. An unanticipated transcriptome shift in microglia reduced gliosis and cerebral inflammation. Significant reductions in the Aβ load, tau phosphorylation, and microglial synapse engulfment prevented memory loss. To summarize, our study describes the pathogenic mechanism of STING activation as well as its potential as a therapeutic target in AD.

AI snapshot

Written from the paper’s full text.

TL;DR

In AD model mice and human iPSC-derived microglia, Aβ, tau, and APOE ε4 activate cGAS-STING, and STING is required for microglial inflammatory, type-I-IFN, and NLRP3 responses. Pharmacological STING inhibition with H-151 in AppNL-G-F/hTau double-knock-in mice reduced gliosis, Aβ burden, tau phosphorylation, synaptic engulfment, and memory impairment.

Key findings

  • cGAS and STING were increased in AppNL-G-F, ADLPAPP/PS1, and AppNL-G-F/hTau dKI brains; cGAMP was significantly elevated in AppNL-G-F cortex (N = 6,6), and cGAS/STING were highly expressed in Aβ plaque-associated microglia.
  • Aβ and tau increased cytoplasmic dsDNA in primary microglia; Aβ induced a proinflammatory followed by type-I-IFN response, while tau induced a type-I-IFN-skewed response. H-151 blocked persistent proinflammatory/IFN responses, iNOS, p-STAT1, ISG15, and NLRP3/IL-1β maturation.
  • APOE ε4/ε4 iMGs had almost twice the cGAS and STING protein levels of ε3/ε3 iMGs without stimulation; STING-KO ε4 iMGs tended to abrogate higher IFNB1/TNFA expression.
  • In 10-month dKI mice, H-151 for 2.5 months reduced Iba1+ and GFAP+ areas, Aβ plaque coverage, Gu-HCl-soluble Aβ40/Aβ42, p-tau at pT181, AT8, pS356, pS396, and pS422, microglial p-STAT1, and PSD95 engulfment, and improved Y-maze and novel object recognition performance (n = 13 per group). Microglial RNA-seq found 34 upregulated and 132 downregulated genes in dKI mice, 434 upregulated genes in WT mice, 5 shared upregulated and 73 shared downregulated transcripts, and 78 STING-dependent microglial genes.

Methods

  • Female AppNL-G-F knock-in and AppNL-G-F/hTau double-knock-in C57BL/6 mice were used; 10-month-old dKI mice received intraperitoneal H-151 at 210 μg (7 mg/kg) three times weekly for 2.5 months. Primary microglia/neurons and human APOE ε3/ε4 iPSC-derived microglia-like cells, including CRISPR STING knockout, were also studied.
  • Main assays included immunoblotting, immunofluorescence, Aβ fractionation/ELISA, cGAMP ELISA, cytoplasmic dsDNA PicoGreen measurement, CD11b+ microglia isolation with RNA-seq (DESeq2, GO, GSEA), and Y-maze/NOR behavioral tests.
  • Statistics used unpaired Student’s t-test, one-way or two-way ANOVA with Tukey’s multiple-comparisons test, or Mann-Whitney test; p ≤ 0.05 was considered significant.

Limitations

  • Stated: the cause of increased neuronal STING in the AD brain remains to be determined; H-151 was given intraperitoneally for 2.5 months, so chronic or peripheral effects may have contributed; the relationship between cGAS-STING and T-cell infiltration was not directly addressed and requires further systematic analysis.
  • Stated: pharmacological STING inhibition unexpectedly increased some chemokines and interferon-stimulated genes in dKI microglia, and it is difficult to determine why Cxcl10 and a few other genes were elevated.
  • Evident: in vivo experiments used female mice only, and the study relies on mouse models and iPSC-derived microglia rather than human AD brain tissue validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s12276-024-01295-y

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

3 of 5 cited sources checked · 3 supported · 0 flagged

  • Findingown data

    cGAS and STING are more highly expressed in ADLPAPP/PS1 mice than in AppNL-G-F mice at similar ages.

    “cGAS and STING were more highly expressed in ADLPAPP/PS1 mice than in AppNL-G-F mice at similar ages, with a pattern similar to that of amyloidosis.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Pharmacological STING inhibition reduced a wide range of AD pathogenic features in AppNL-G-F/hTau double-knock-in mice.

    “Pharmacological STING inhibition reduced a wide range of AD pathogenic features in AppNL-G-F/hTau double-knock-in mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    Aβ and tau induce different profiles of cGAS-STING downstream activation.

    “Aβ and tau induced different profiles of GAS-STING downstream activation.”
    Quote in the paperSubstantial claim
  • Findingown data

    cGAS and STING protein levels are also increased in AppNL-G-F/hTau-dKI mice.

    “we further utilized AppNL-G-F/hTau-dKI mice and found the same expression patterns”
    Quote in the paperSubstantial claim
  • Findingown data

    The presence of the APOE ε4 allele upregulates cGAS and STING proteins.

    “The presence of the APOE ε4 allele, an AD risk factor, also upregulated both proteins.”
    • Also stated in: § STING knockout reversed the reduced reactivity of APOE ε4 human iPSC-derived microglia · plain
      “the levels of the cGAS and STING proteins were almost twice as high in APOE ε4/ε4 iMGs than in ε3/ε3 iMGs in the absence of any stimulation”
    Quote in the paperSubstantial claim
    • Rests on an assumption: APOE ε4 is the single strongest genetic risk factor for late-onset AD.
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 5
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Stimulation of the cGAS-STING pathway induces microglial dysfunction and sterile inflammation, which exacerbates AD.

    “Stimulation of the cGAS-STING pathway induces microglial dysfunction and sterile inflammation, which exacerbates AD.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [19] Xie, X. et al. Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice. Nat. Aging 3, 202–212 (2023). source
    • cites [20] Udeochu, J. C. et al. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. Nat. Neurosci. 26, 737–750 (2023). source
    • Rests on an assumption: Abnormal immune activation is a consistent feature of neurodegenerative diseases, including AD.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Potential ex vivo activation was inhibited as described in a previous study.

    “Potential ex vivo activation was inhibited as described in a previous study25 (Supplementary Fig. 7c).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] Marsh, S. E. et al. Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain. Nat. Neurosci. 25, 306–316 (2022). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The interferon-responsive microglial state is not an artifact of ex vivo activation.

    “the interferon-responsive microglial state has been steadily reported, and this state is not an artifact of ex vivo activation25.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Marsh, S. E. et al. Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain. Nat. Neurosci. 25, 306–316 (2022). source

  • May combine two claims.

    Findingown data

    STING activation is necessary for microglial NLRP3 activation, proinflammatory responses, and type-I-interferon responses.

    “STING activation was necessary for microglial NLRP3 activation, proinflammatory responses, and type-I-interferon responses.”
    • Also stated in: § Aβ and tau increased cytoplasmic DNA levels and induced distinct activation of microglia, which is dependent on STING · plain
      “In summary, NLRP3 activation and proinflammatory and interferon responses are mitigated by targeting STING.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Senescence marker genes Cdkn1a and Cdkn2a and cGAS-STING downstream response genes Irf7, Stat1, Ifitm3, Cxcl10 are upregulated in dKI microglia, and Enpp1 is upregulated.

    “The senescence marker genes (Cdkn1a, Cdkn2a) and cGAS-STING pathway downstream response genes (Irf7, Stat1, Ifitm3, Cxcl10) were upregulated in dKI microglia, and the expression of the cGAMP-degrading enzyme Enpp1 was also upregulated”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    cGAS, STING and γH2AX levels are all increased in hippocampi of 8-month-old ADLPAPP/PS1 mice.

    “cGAS, STING and γH2AX levels were all increased in the hippocampi of 8-month-old ADLPAPP/PS1 mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 4.5-month-old ADLPAPP/PS1 mice, cGAS and STING are already increased but γH2AX levels do not differ from WT.

    “However, in the brains of 4.5-month-old ADLPAPP/PS1 mice, in which cGAS and STING protein levels were already increased, γH2AX levels did not differ from those in the brains of WT mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ induces a proinflammatory response followed by type-I-IFN response, while tau induces a type-I IFN-skewed response.

    “In terms of gene expression profiles, Aβ induced a proinflammatory response followed by a type-I-IFN response, while tau induced a type-I IFN-skewed response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TBK1 and p65 phosphorylation are strongly activated by Aβ, but mild in tau-treated microglia.

    “TBK1 and p65 phosphorylation were strongly activated by Aβ, but their phosphorylation was mild in tau-treated microglia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    dsDNA and p-tau are present within Aβ plaques in dKI mice.

    “Immunostaining of the brains of dKI mice confirmed the presence of dsDNA and p-tau within the Aβ plaques”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    STING inhibition has negligible effect on Aβ-induced gene expression at early timepoint but attenuates persistent proinflammatory and type I IFN responses at 24 h.

    “STING inhibition had a negligible effect on Aβ-induced gene expression at the early timepoint but effectively attenuated persistent proinflammatory and type I IFN responses at the 24 h timepoint.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    cGAS is upregulated by both Aβ and tau; STING is slightly downregulated by Aβ but upregulated by tau.

    “cGAS was upregulated by both Aβ and tau, but STING was slightly downregulated by Aβ but upregulated by tau.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both Aβ and tau induce IRF3 and STAT1 phosphorylation.

    “Both Aβ and tau induced IRF3 and STAT1 phosphorylation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The brain STING protein level was inversely correlated with the PSD95 level but positively correlated with the NLRP3 level.

    “The brain STING protein level was inversely correlated with the PSD95 level but positively correlated with the NLRP3 level”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The level of TBS-soluble Aβ42 tended to increase, but the difference was not significant.

    “The level of TBS-soluble Aβ42 tended to increase, but the difference was not significant”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    When stimulated with Aβ, ε4 iMGs express more TNFA than ε3 iMGs.

    “When iMGs were stimulated with Aβ, ε4 iMGs expressed TNFA than ε3 iMGs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the WT mouse group, 434 genes were upregulated.

    “In the WT mouse group, 434 genes were upregulated”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Aβ and tau increased cytoplasmic mtDNA through different kinetics and the activator of different downstream kinases.

    “but through different kinetics and the activator of different downstream kinases”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CXCL10 signal strongly overlapped with that of astrocytes and was reduced by H-151.

    “brain staining revealed that the CXCL10 signal strongly overlapped with that of astrocytes and was reduced by H-151”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    STING inhibition did not change the total tau level but significantly reduced tau phosphorylation.

    “STING inhibition did not change the total tau level but significantly reduced tau phosphorylation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    STING inhibition reduced Aβ aggregation and tau phosphorylation.

    “Our data showed that STING inhibition reduced Aβ aggregation and tau phosphorylation (Fig. 6c–i).”
    • Also stated in: § STING inhibition ameliorated AD pathology and cognitive impairment in AppNL-G-F/hTau-dKI mice · plain
      “pharmacological inhibition of STING in dKI mice significantly reduced the Aβ burden and tau hyperphosphorylation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cxcl10, Ccl12, Iigp1, Lox2, and Spp1 were highly expressed in AD microglia and further upregulated after H-151 administration.

    “Cxcl10, Ccl12, Iigp1, Lox2, and Spp1 were highly expressed in AD microglia and further upregulated after H-151 administration”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Control dKI mice exhibited memory impairment, while H-151-injected dKI mice exhibited improved memory function.

    “While control dKI mice exhibited memory impairment, H-151-injected dKI mice exhibited improved memory function”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    No significant weight loss is observed after H-151 injection.

    “No significant weight loss was observed after injection”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The Aβ burden, tau hyperphosphorylation and abnormal synapse loss were suppressed by pharmacological STING inhibition.

    “the Aβ burden, tau hyperphosphorylation and abnormal synapse loss, which are widespread pathological features of AD, were suppressed by pharmacological STING inhibition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ-induced iNOS is upregulated by cGAMP in a dose-dependent manner, and H-151 and SN-011 decrease iNOS levels.

    “Aβ-induced iNOS was upregulated by cGAMP in a dose-dependent manner, and the STING antagonists H-151 and SN-011 both robustly decreased iNOS levels”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both Aβ and tau increased the amount of cytoplasmic mtDNA.

    “Both Aβ and tau increased the amount of cytoplasmic mtDNA”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    STING was found to be strongly required for microglial proinflammatory activity, type-I-IFN responses and NLRP3 activation.

    “STING was found to be strongly required for microglial proinflammatory activity, type-I-IFN responses and NLRP3 activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Both Aβ and tau, as well as the APOE ε4 allele, were linked to increases in cGAS and STING levels in human microglia.

    “Both Aβ and tau, as well as the APOE ε4 allele, were linked to increases in cGAS and STING levels in human microglia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    STING was required for Aβ and p-tau accumulation and microglial synapse engulfment.

    “STING was required for Aβ and p-tau accumulation and microglial synapse engulfment (Fig. 8a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Significant STING expression is observed in neurons but not astrocytes in vivo.

    “Surprisingly, however, significant STING expression was observed in neurons but not in astrocytes in vivo”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neurons show increased IFITM3 in response to cGAMP, whereas MX1 is not affected.

    “neurons showed an increase in IFITM3 in response to cGAMP, whereas another interferon-inducible protein, MX1, was not affected”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both iPSCs and iMGs express cGAS, but differences in cGAS expression are detected only in iMGs; STING expression is limited in iMGs.

    “both iPSCs and iMGs expressed cGAS, but differences in cGAS expression were detected only in iMGs. STING expression was limited in iMGs”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    H-151 crosses the blood-brain barrier and affects the brain, as shown by reduction in brain p-TBK1 levels.

    “The reduction in brain p-TBK1 levels confirmed that H-151 was able to cross the BBB and affect the brain”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    STING inhibitor-treated mice exhibited preserved working memory and object recognition memory.

    “the STING inhibitor-treated mice exhibited preserved working memory and object recognition memory (Fig. 6a, b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Higher levels of the postsynaptic component PSD95 and lower NLRP3 levels were observed in the brains of STING-inhibited dKI mice.

    “Higher levels of the postsynaptic component PSD95 and had lower NLRP3 levels were observed in the in brains of STING-inhibited dKI mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the WT mouse group, Xlr4c, Atp2a3, Rfwd3, and Insig1 were upregulated, while Malat1, Rnf25, Bax, Ly9, and Isg15 were downregulated.

    “In the WT mouse group, Xlr4c, Atp2a3, Rfwd3, and Insig1 were upregulated, while Malat1, Rnf25, Bax, Ly9, and Isg15 were downregulated”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    dKI mice had disrupted PSD95 patterns and microglia with an enlarged CD68+ lysosomes compared to WT mice.

    “Compared to WT mice with clear dendritic PSD95 patterns, dKI mice had disrupted PSD95 patterns and microglia with an enlarged CD68+ lysosomes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Successive Aβ and cGAMP treatment induced IL-1β maturation and vice versa.

    “successive Aβ and cGAMP treatment induced IL-1β maturation and vice versa.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Both Aβ and tau increase ectopic DNA in cytoplasm, while Aβ induces clear morphological changes in mitochondria.

    “Thus, both Aβ and tau were able to increase ectopic DNA in the cytoplasm, while Aβ induced clear morphological changes in mitochondria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The cGAS-STING pathway is strongly involved in Aβ-induced tau phosphorylation, dendritic tau accumulation, and abnormal microglial synapse engulfment.

    “our data suggest that the cGAS-STING pathway is strongly involved in these phenomena.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Peritoneal injection of the STING inhibitor H-151 induced an unexpected shift in the brain microglial transcriptome while reducing overall glial reactivity and brain inflammation.

    “peritoneal injection of the STING inhibitor H-151 induced an unexpected shift in the brain microglial transcriptome while reducing overall glial reactivity and brain inflammation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The cGAS-STING pathway may be involved in reduced ε4 microglial responsiveness and may be affected by the APOE ε4 allele in addition to Aβ, tau, and age.

    “These results indicate that the cGAS-STING pathway may be involved in reduced ε4 microglial responsiveness and may be affected by the APOE ε4 allele in addition to Aβ, tau, and age.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: APOE ε4 is the single strongest genetic risk factor for late-onset AD.

  • May combine two claims.

    Interpretationown data

    Neuronal STING is upregulated in AD model mice, and STING activation can induce IFITM3 expression.

    “To summarize, neuronal STING is upregulated in the brains of AD model mice, and STING activation can induce IFITM3 expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Pharmacological inhibition of STING effectively reduced microglial p-STAT1 levels and postsynaptic engulfment, which is consistent with the results of the behavioral tests.

    “pharmacological inhibition of STING effectively reduced microglial p-STAT1 levels and postsynaptic engulfment, which is consistent with the results of the behavioral tests.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Pharmacological inhibition of STING in dKI mice significantly reduced the Aβ burden and tau hyperphosphorylation and preserved memory function.

    “pharmacological inhibition of STING in dKI mice significantly reduced the Aβ burden and tau hyperphosphorylation and preserved memory function.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Hyperphosphorylated tau, rather than normal tau, contributes to synaptic dysfunction and loss.
    • Rests on an assumption: Aβ-induced tau hyperphosphorylation is closely associated with synapse loss and memory impairment in AD.
46 of 46

  • The paper relies on this without support.

    APOE ε4 is the single strongest genetic risk factor for late-onset AD.

    “the APOE ε4 allele, the single strongest genetic risk factor for late-onset AD (LOAD)”

  • The paper relies on this without support.

    Abnormal immune activation is a consistent feature of neurodegenerative diseases, including AD.

    “Abnormal immune activation is a consistent feature of neurodegenerative diseases, including Alzheimer’s disease (AD).”

  • The paper relies on this without support.

    The cGAS-STING pathway is a common denominator among diverse AD-associated factors.

    “In searching for a common denominator among these diverse factors, we focused on the immune response against ectopic DNA and specifically the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.”

  • The paper relies on this without support.

    Hyperphosphorylated tau, rather than normal tau, contributes to synaptic dysfunction and loss.

    “hyperphosphorylated tau, rather than normal tau, contributes to synaptic dysfunction and loss.”

  • The paper relies on this without support.

    Aβ-induced tau hyperphosphorylation is closely associated with synapse loss and memory impairment in AD.

    “Aβ-induced tau hyperphosphorylation is closely associated with synapse loss and memory impairment in AD”

  • The paper relies on this without support.

    Both amyloid and tau are key players in AD pathogenesis, and their interaction results in different outcomes than those induced by each factor individually.

    “Both amyloid and tau are key players in AD pathogenesis, and their interaction results in different outcomes than those induced by each factor individually.”

  • The paper relies on this without support.

    Pharmacological targeting or genetic ablation of cGAS and STING tends to be protective in diverse neural disorders.

    “Pharmacological targeting or genetic ablation of cGAS and STING tends to be protective in diverse neural disorders.”

  • The paper relies on this without support.

    Maturation of IL-1β is dependent on NLRP3 activation.

    “The maturation of IL-1β is dependent on NLRP3 activation”

  • The paper relies on this without support.

    STING activation leads to NLRP3 inflammasome activation.

    “STING activation leads to NLRP3 inflammasome activation.”

  • The paper relies on this without support.

    Aβ can activate TLR4, which is located upstream of TBK1 and p65, causing excessive phosphorylation.

    “Aβ can activate TLR4, which is located upstream of TBK1 and p65, causing excessive phosphorylation.”

  • The paper relies on this without support.

    Chemokines such as CXCL10, which attracts infiltrating T cells, are known downstream effectors of STING.

    “chemokines such as CXCL10, which attracts infiltrating T cells, are known downstream effectors of STING.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Pharmacological inhibition of STING activation reduces microglia-mediated inflammatory response and ameliorates a wide range of Alzheimer's disease-related symptoms in AppNL-G-F/hTau double-knock-in mice.

    “For example, pharmacological inhibition of STING activation reduces microglia‐mediated inflammatory response and ameliorates a wide range of AD‐related symptoms in AppNL−G−F/hTau double‐knock‐in mice [68].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [68]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Cytoplasmic DNA imaging cites the wrong figure panel

    Minor

    The text cites Fig. 2d for the DAPI- and Tom20-negative DNA signals, whereas the figure caption assigns that measurement to Fig. 2b. Fig. 2d is the cytoplasmic dsDNA assay.

  • Cytoplasmic DNA assay cites protein-blot panels

    Minor

    The text cites Fig. 2e and f for cytoplasmic DNA measurements, but the caption identifies those panels as cGAS-STING protein blots and their quantification. It assigns the cytoplasmic dsDNA measurement to Fig. 2d.

2 of 2

Cites

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Authors
Chung, S., Jeong, J.-H., Park, J.-C., Han, J. W., Lee, Y., Kim, J.-I., & Mook-Jung, I.
Affiliations
  • Seoul National University (KR)
  • Sungkyunkwan University (KR)
ORCID
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2024-09-02
Volume
56
Issue
9
Pages
1936-1951
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-024-01295-y
PMC
PMC11447230
OpenAlex
W4402143990
Cited by
103
References
65
Citations by year
2026: 64 · 2025: 39
FWCI
13.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
  • National Research Foundation
  • Seoul National University
  • Ministry of Education (2020R1A6A3A13070845)
  • Ministry of Science, ICT and Future Planning (HU23C1234)
  • Ministry of Health and Welfare (HU23C1234)
  • Korea Basic Science Institute (2021R1A6C101A445)
  • National Research Foundation of Korea
  • Ministry of Science and ICT, South Korea (RS‐2020‐KH106747)
  • RIKEN
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, STING, cGAS-STING pathway, microglial dysfunction, sterile inflammation, amyloid-beta, tau phosphorylation, mitochondrial stress, APOE ε4, NLRP3 inflammasome, type I interferon, gliosis, synapse engulfment, memory loss, STING inhibition, therapeutic target
MeSH terms
STING Protein, Alzheimer Disease, Animals, Disease Models, Animal, Humans, Membrane Proteins, Mice, Transgenic, Nucleotidyltransferases, Signal Transduction, Amyloid beta-Peptides, Microglia, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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