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Cited by 144Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology

Open access
Maphis, Nicole, Jiang, Shanya, Xu, Guixiang, Kokiko-Cochran, Olga N., Roy, Saktimayee M., Van Eldik, Linda J., Watterson, D. Martin, Lamb, Bruce T. +1 more·2016·Alzheimer's Research & Therapy
DOI 10.1186/s13195-016-0221-yPMC PMC5157054
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Abstract

Background: Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1. Method: We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice. Results: First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 (pS199/pS202) site tau phosphorylation, with the maximum effect peaking at 60–90 min after stimulation. Second, treatment of old (~20 months of age) hTau mice with MW181 (1 mg/kg body weight; 14 days via oral gavage) significantly reduced p38α MAPK activation compared with vehicle-administered hTau mice. This also resulted in a significant reduction in AT180 (pT231) site tau phosphorylation and Sarkosyl-insoluble tau aggregates. Third, MW181 treatment significantly increased synaptophysin protein expression and resulted in improved working memory. Fourth, MW181 administration reduced phosphorylated MAPK-activated protein kinase 2 (pMK2) and phosphorylated activating transcription factor 2 (pATF2), which are known substrates of p38α MAPK. Finally, MW181 reduced the expression of interferon-γ and interleukin-1β. Conclusions: Taken together, these studies support p38α MAPK as a valid therapeutic target for the treatment of tauopathies.

AI snapshot

Written from the paper’s full text.

TL;DR

MW181, an isoform-selective p38α MAPK inhibitor, reduced inflammation-induced tau phosphorylation in primary neurons and, after 14 days of oral treatment, reduced tau phosphorylation/aggregation and improved working memory in aged hTau mice. The authors conclude that p38α MAPK is a valid therapeutic target for tauopathies.

Key findings

  • In primary cortical neurons, pretreatment with MW181 (2 μM) or SB239063 (100 μM) blocked Cx3cr1−/− microglial conditioned media-induced AT8 (pS199/pS202) and AT180 (pT231) tau phosphorylation; MW181’s maximum reduction of p38α MAPK (pT180/pY182) and AT8 tau phosphorylation occurred at 60–90 min after stimulation.
  • In 20-month-old hTau mice, MW181 (1 mg/kg body weight, oral gavage, 14 days) significantly reduced AT180/Tau5 ratio (n = 6 MW181, n = 6 vehicle, n = 4 SB239063; p < 0.01), reduced Sarkosyl-insoluble tau (Tau5 ratio; n = 7 MW181, n = 5 vehicle, n = 3 SB239063; p < 0.01, *p < 0.001, p < 0.0001), increased synaptophysin, and improved Y-maze spontaneous alternation versus vehicle (n = 6 MW181, n = 5 vehicle, n = 4 SB239063; *p < 0.05).
  • MW181 significantly reduced hippocampal pATF2 (pT71) and pMK2 (pT334) and reduced IFNγ and IL-1β expression in aged hTau mice, while in vivo p-p38α MAPK (pT180/pY182) levels did not significantly decrease.
  • MK2−/− mice were resistant to LPS-induced AT8 and AT180 tau phosphorylation and showed significantly reduced total p38α MAPK levels compared with nontransgenic mice.

Methods

  • In vitro: primary cortical neurons from E16.5 C57BL/6J embryos grown 21 DIV; microglia from P3 Cx3cr1−/− pups; neurons pretreated 30 min with MW181 (2 μM), SB239063 (100 μM), or vehicle, then stimulated with 25% Cx3cr1−/− microglial conditioned media; lysates analyzed by western blot.
  • In vivo: 20-month-old hTau mice received MW181 (1 mg/kg), SB239063 (5 mg/kg), or saline daily by oral gavage for 14 days; hippocampi analyzed by western blot, Sarkosyl-insoluble assay, qPCR, immunohistochemistry/immunofluorescence, and Y-maze. Separate 2-month-old nontransgenic and MK2−/− mice received LPS (10 mg/kg i.p.) or vehicle.
  • Statistics: unpaired t tests and one-way or two-way ANOVA with indicated post-hoc tests using GraphPad Prism.

Limitations

  • Stated: the authors note this is the first study targeting p38α MAPK in a 20-month-old tauopathy model and should be validated by a separate group; they did not compare MW181 effects in nontransgenic mice; MW181 did not completely abolish activated p38α MAPK; and only one MW181 dose (1 mg/kg) was tested.
  • Stated: the authors note that different dosing and treatment durations are key considerations for pharmacological safety.
  • Evident from the text: some treatment groups had small sample sizes (e.g., SB239063 n = 3–4 in several assays), mixed genders were used, and no dose-response or long-term safety/toxicity assessment beyond weight, grooming, and posture monitoring is reported.

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

Integrity signals

Registry

Crossref · 10.1186/s13195-016-0221-y

Cites

70 of 70 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

31 of 40 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Signaling through p38 MAPK, especially the p38α isoform, is a critical component for cytokine production in activated microglia.

    “Signaling through p38 MAPK, especially the p38α isoform, has also been discovered recently to be a critical component for cytokine production in activated microglia [25, 26].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [25] Roy SM, Grum-Tokars VL, Schavocky JP, Saeed F, Staniszewski A, Teich AF, Arancio O, Bachstetter AD, Webster SJ, Van Eldik LJ, et al. Targeting human central nervous system protein kinases: An isoform selective p38alphaMAPK inhibitor that attenuates disease progression in Alzheimer’s disease mouse models. ACS Chem Neurosci. 2015;6(4):666–80. source
    • cites [26] Watterson DM, Grum-Tokars VL, Roy SM, Schavocky JP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E, Saeed F, Zhang H, et al. Development of novel chemical probes to address CNS protein kinase involvement in synaptic dysfunction. PLoS One. 2013;8(6), e66226. source
  • Premisecitation

    p38α-mediated cytokine overproduction in microglia has been linked to inflammation-induced neurotoxicity in a variety of mouse models.

    “The p38α-mediated cytokine overproduction in microglia has been linked to inflammation-induced neurotoxicity in a variety of mouse models [22, 27–33].”
    Quote in the paperSubstantial claim5 of 8 sources checked
    • cites [22] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31. source

      The Results section on TLR4 and IL1 signaling links microglial IL1 to neuronal p38 MAPK activation and tau phosphorylation; it also reports earlier findings linking IL1β from LPS-stimulated microglia to neurotoxicity. The paper does not establish that p38α in microglia causes cytokine overproduction or show this neurotoxic mechanism across a variety of mouse models. Page numbers are not available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [27] Xing B, Bachstetter AD, Van Eldik LJ. Microglial p38alpha MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFalpha. Mol Neurodegener. 2011;6:84. source

      The Discussion reports that p38α-dependent TNFα production in mouse microglia–neuron co-cultures contributes to LPS-induced neuronal damage. The Background also mentions an earlier AD-relevant mouse model, but this paper does not itself establish the link across a variety of mouse models. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [28] Bachstetter AD, Watterson DM, Van Eldik LJ. Target engagement analysis and link to pharmacodynamic endpoint for a novel class of CNS-penetrant and efficacious p38alpha MAPK inhibitors. J Neuroimmune Pharmacol. 2014;9(4):454–60. source

      The Introduction explicitly links microglial p38α-mediated cytokine overproduction to inflammation-induced neurotoxicity, citing earlier studies. It also describes protection in a mouse brain-injury model, but does not establish this neurotoxicity link across a variety of mouse models. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [29] Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ. Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Abeta). J Neuroinflammation. 2011;8:79. source

      The Background links microglial cytokine overproduction to neuronal death and reports improved neurological outcomes after p38α inhibition in an Alzheimer’s-relevant mouse model. This paper also demonstrates p38α-dependent cytokine production, but its own in vivo experiment measures cytokines in one LPS-induced mouse model, not neurotoxicity across a variety of mouse models. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [30] Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S, Badger AM, Legos JJ, Erhardt JA, Ohlstein EH, et al. Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia. Med Res Rev. 2001;21(2):129–45. source
    • cites [31] Correa SA, Eales KL. The role of p38 MAPK and its substrates in neuronal plasticity and neurodegenerative disease. J Signal Transduct. 2012;2012:649079. source

      Section 3.2 links p38 MAPK activation in glial cells to increased inflammatory cytokines and potential neuronal toxicity; it also reports that a selective p38α inhibitor blocks increased inflammatory-molecule production. The neurotoxicity examples described there involve glial cultures and rat brains, not a variety of mouse models. No page numbers are provided in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [32] Dewil M, dela Cruz VF, Van Den Bosch L, Robberecht W. Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death. Neurobiol Dis. 2007;26(2):332–41. source
    • cites [33] Stirling DP, Liu J, Plunet W, Steeves JD, Tetzlaff W. SB203580, a p38 mitogen-activated protein kinase inhibitor, fails to improve functional outcome following a moderate spinal cord injury in rat. Neuroscience. 2008;155(1):128–37. source
  • Premisecitation

    MW181 is a highly selective p38α MAPK inhibitor.

    “MW01-10-181SRM (or MW181), a highly selective p38α MAPK inhibitor [26]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Watterson DM, Grum-Tokars VL, Roy SM, Schavocky JP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E, Saeed F, Zhang H, et al. Development of novel chemical probes to address CNS protein kinase involvement in synaptic dysfunction. PLoS One. 2013;8(6), e66226. source

      The Results section identifies MW181 as a p38αMAPK inhibitor, but describes it as a p38MAPK subfamily inhibitor rather than an isoform-selective one. Kinase profiling found similar inhibitory affinities for p38αMAPK, p38βMAPK, and NLK; the paper identifies MW108, not MW181, as more selective for p38αMAPK. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    p38α MAPK has been shown to mediate Aβ-induced expression of various proinflammatory cytokines/chemokines from microglial cells that causes neuroinflammation.

    “First, p38α MAPK has been shown to mediate Aβ-induced expression of various proinflammatory cytokines/chemokines from microglial cells that causes neuroinflammation [25, 26, 29, 35].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [25] Roy SM, Grum-Tokars VL, Schavocky JP, Saeed F, Staniszewski A, Teich AF, Arancio O, Bachstetter AD, Webster SJ, Van Eldik LJ, et al. Targeting human central nervous system protein kinases: An isoform selective p38alphaMAPK inhibitor that attenuates disease progression in Alzheimer’s disease mouse models. ACS Chem Neurosci. 2015;6(4):666–80. source

      The Methods (Cell Based Activity) and Results and Discussion (Kinome Target Selectivity; page unavailable) show that inhibiting p38αMAPK signaling reduced proinflammatory IL-1β production in LPS-stimulated microglial cells. They do not show Aβ-induced production of various cytokines or chemokines by microglia, or establish that this production causes neuroinflammation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] Watterson DM, Grum-Tokars VL, Roy SM, Schavocky JP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E, Saeed F, Zhang H, et al. Development of novel chemical probes to address CNS protein kinase involvement in synaptic dysfunction. PLoS One. 2013;8(6), e66226. source

      The Results section on CNS mechanism of action links microglial p38αMAPK to increased proinflammatory cytokine production, but the experiments described there use LPS or TLR ligands and measure IL-1β. The Results section on amyloid-beta elevation reports rescue of Aβ-induced synaptic deficits, not Aβ-induced microglial expression of various cytokines or chemokines. The References identify a separate study on Aβ-induced microglial cytokine up-regulation; this paper does not itself establish the full claim. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [29] Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ. Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Abeta). J Neuroinflammation. 2011;8:79. source

      The Figure 4 caption reports that inhibiting p38α MAPK suppressed Aβ1-42-induced increases in IL-1β and TNFα in primary microglia. The Methods and Results address those two cytokines, not Aβ-induced chemokine expression; the in vivo neuroinflammation model used LPS rather than Aβ, so the claimed Aβ-driven neuroinflammation was not directly shown. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [35] Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM. A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model. J Neuroinflammation. 2007;4:21. source

      The Background reports that Aβ activates p38 MAPK in glial cultures, followed by increased proinflammatory cytokines that p38 inhibitors block. The Results and Discussion report that a p38α inhibitor reduced Aβ-induced hippocampal cytokines in mice. The paper does not establish that those mouse cytokines came specifically from microglia, and the cited passages do not support the claim about chemokines. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingcitation

    Cx3cr1-/- microglial conditioned media significantly induced tau phosphorylation on AT8 and AT180 sites.

    “As reported previously [22], exchange of 25% of the neuronal supernatant with Cx3cr1 –/– microglia CM led to an increase in tau phosphorylation on S199/S202 (AT8) and T231 (AT180) sites (Fig. 1d, e).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31. source

      The Experimental Procedures describe replacing 25% of neuronal medium with microglial conditioned medium. The Results report that medium from Cx3cr1−/− microglia enhanced neuronal tau phosphorylation at AT8 and PHF1, not AT180. The paper reports AT180 increases in mice under other conditions, but not in this conditioned-medium experiment; page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 29
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Neocortical neurons pretreated with SB203580 and then treated with interleukin-1β showed significantly reduced tau phosphorylation and restored synaptophysin levels.

    “This is consistent with a previous in vitro study in which neocortical neurons pretreated with the popular-mixed kinase inhibitor SB203580 and then treated with interleukin-1β (IL-1β) showed significantly reduced tau phosphorylation and restored synaptophysin levels [24].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci. 2003;23(5):1605–11. source

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

    Premisecitation

    NFT pathology closely correlates with neurodegeneration and cognitive decline.

    “Recent studies suggest that NFT pathology closely correlates with neurodegeneration and cognitive decline [1, 2].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [1] Murray ME, Lowe VJ, Graff-Radford NR, Liesinger AM, Cannon A, Przybelski SA, Rawal B, Parisi JE, Petersen RC, Kantarci K, et al. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum. Brain. 2015;138(Pt 5):1370–81. source

      The Discussion reports a strong association between NFT accumulation and cognitive decline, and finds that higher Braak NFT stage predicts lower MMSE scores. It describes cortical NFTs as an example of significant neurodegeneration, but does not report a correlation between NFT pathology and an independent measure of neurodegeneration. Page numbers were not available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [2] Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362–81. source

  • May combine two claims.

    Premisecitation

    Elevated levels of active (phosphorylated) p38α MAPK, but not GSK3β or regulators (p35/p25) of Cdk5, correlate with increased tau phosphorylation in the hippocampus of hTau mice deficient for CX3CR1.

    “Notably, we observed elevated levels of active (phosphorylated) p38α MAPK, but not GSK3β or regulators (p35/p25) of Cdk5, correlating with increased tau phosphorylation in the hippocampus of hTau mice deficient for the chemokine receptor CX3CR1 [22].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31. source

      The Results section, “Elevated p38 MAPK signaling in hTau-Cx3cr1−/− transgenic mice” (page unavailable), reports increased hippocampal phospho-p38 MAPK in six-month-old CX3CR1-deficient hTau mice, alongside increased tau phosphorylation; p35/p25 and phospho-ser9 GSK3β were unchanged. It does not identify the elevated p38 signal specifically as p38α, and the unchanged GSK3β measurement is limited to its serine-9-phosphorylated form. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 MAPK in the hTau mouse model of tauopathy deficient for microglial fractalkine receptor CX3CR1.

    “We have demonstrated recently that activated microglia induced tau hyperphosphorylation via activation of the p38α MAPK signaling pathway in the hTau mouse model of tauopathy [22, 23].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [22] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31. source

      The Results section on microglial factors shows that blocking p38 MAPK prevents the tau phosphorylation induced by factors from CX3CR1-deficient microglia. The Results section on worsened disease reports impaired spatial working memory in CX3CR1-deficient hTau mice, but does not establish that p38 MAPK caused that impairment. The paper identifies p38 MAPK, not specifically the p38α isoform. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [23] Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015;138(Pt 6):1738–55. source

      The Introduction reports that CX3CR1 deficiency in hTau mice increased microglial activation, accelerated tau pathology, and impaired working memory; it says mechanistic studies suggested involvement of IL-1R–p38 MAPK signaling. The Results also report that blocking IL-1 signaling reduced microglia-induced tau hyperphosphorylation alongside reduced p38 MAPK activation. The paper does not establish the cited sentence’s p38α-specific mechanism or show that cognitive impairment occurs via that pathway. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    More than 20 serine/threonine kinases are reported to phosphorylate tau in vitro, including GSK-3β, Cdk5, MARK1-4, ERK, p38α MAPK, and JNK.

    “In fact, there are currently more than 20 serine/threonine kinases reported to phosphorylate tau in vitro: glycogen synthase kinase 3 beta (GSK-3β), cyclin-dependent kinase 5 (Cdk5), microtubule affinity regulating kinase 1–4 (MARK1–MAPK4), extracellular signal-related kinase (ERK), p38 mitogen-associated protein kinase alpha (p38α MAPK), and c-Jun N-terminal kinase (JNK) are the best examples [19”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [19] Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol. 1999;58(9):1010–9. source
    • cites [20] Pei JJ, Grundke-Iqbal I, Iqbal K, Bogdanovic N, Winblad B, Cowburn RF. Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer’s disease neurofibrillary degeneration. Brain Res. 1998;797(2):267–77. source
    • cites [21] Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802(4):396–405. source

      Section 2.1 (Alzheimer’s disease; page not provided) says that JNK, p38, and ERK mediate tau phosphorylation. It does not give a count of more than 20 kinases, specify in-vitro evidence, or identify GSK-3β, Cdk5, MARK1–4, or specifically p38α as tau kinases. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Targeted inactivation of p38α MAPK with small molecule inhibitors prevents the production of proinflammatory cytokines, reduces neurodegeneration, and improves neuronal and cognitive functions in rodent models of amyloid pathology.

    “Targeted inactivation of p38α MAPK with small molecule inhibitors prevents the production of proinflammatory cytokines, reduces neurodegeneration, and improves neuronal and cognitive functions in rodent models of amyloid pathology [25, 26, 29, 35].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [25] Roy SM, Grum-Tokars VL, Schavocky JP, Saeed F, Staniszewski A, Teich AF, Arancio O, Bachstetter AD, Webster SJ, Van Eldik LJ, et al. Targeting human central nervous system protein kinases: An isoform selective p38alphaMAPK inhibitor that attenuates disease progression in Alzheimer’s disease mouse models. ACS Chem Neurosci. 2015;6(4):666–80. source

      In Results and Discussion (page unavailable), the paper reports that MW150 attenuated proinflammatory IL-1β production in cultured microglia and improved memory performance in two amyloid-related mouse models. It does not show that cytokine production was prevented in those mice or that neurodegeneration was reduced; improvement in neuronal function is discussed through earlier work rather than demonstrated here. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [26] Watterson DM, Grum-Tokars VL, Roy SM, Schavocky JP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E, Saeed F, Zhang H, et al. Development of novel chemical probes to address CNS protein kinase involvement in synaptic dysfunction. PLoS One. 2013;8(6), e66226. source

      The Results sections on in vivo efficacy and CNS mechanism (page numbers unavailable) report that p38α MAPK inhibitors rescued amyloid-β-induced synaptic and memory deficits in mice and suppressed stressor-induced IL-1β increases. They do not show reduced neurodegeneration, and the cytokine experiments used LPS or other TLR stimuli rather than an amyloid-pathology model; suppression of elevated IL-1β is also narrower than preventing cytokine production. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [29] Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ. Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Abeta). J Neuroinflammation. 2011;8:79. source

      The Background (page unavailable) reports that the small-molecule p38α inhibitor 069A reduced Aβ-induced cytokine up-regulation, synaptic dysfunction, and behavioral deficits in an AD-relevant mouse model. The paper does not report that the inhibitor reduced neurodegeneration in that model, and its reported cytokine effect is attenuation rather than complete prevention. Its own in vivo experiment, described in the Discussion (page unavailable), tested cytokine responses to LPS, not amyloid pathology. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [35] Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM. A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model. J Neuroinflammation. 2007;4:21. source

      In Results and Discussion, ‘In vivo efficacy in AD animal model’ (page not provided), the paper reports that a p38α MAPK inhibitor reduced Aβ-induced hippocampal cytokine increases, attenuated synaptophysin loss, and improved Y-maze performance in a mouse model. It reports reduction toward baseline, not prevention of cytokine production, and does not show reduced neurodegeneration or test multiple rodent models. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    hTau mice exhibit various behavioral and cognitive impairments by 20 months of age.

    “Previous studies have suggested that hTau mice exhibit various behavioral and cognitive impairments by 20 months of age [52].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] Polydoro M, Acker CM, Duff K, Castillo PE, Davies P. Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology. J Neurosci. 2009;29(34):10741–9. source

  • May combine two claims.

    Premisecitation

    Hyperphosphorylation of tau in this model was mediated by upregulation of p38α the MAPK pathway, but not GSK3β or CDK5 pathways.

    “Furthermore, hyperphosphorylation of tau in this model was mediated by upregulation of p38α the MAPK pathway, but not GSK3β or CDK5 pathways [22].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68(1):19–31. source

      The Results section on elevated p38 MAPK signaling reports increased activated p38 MAPK in hTau-Cx3cr1−/− mice, while the measured GSK3β and Cdk5-regulator markers were unchanged. The cell-culture Results show p38 MAPK-dependent tau phosphorylation, but the paper does not identify the α isoform or establish that p38α mediated the effect in the mice. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Adoptive transfer of reactive microglia from hTau-Cx3cr1 -/- mice led to induction of tau hyperphosphorylation and aggregation within the brains of recipient mice, which was also mediated via the IL-1β-p38α MAPK signaling pathway.

    “In a recent study, we demonstrated that adoptive transfer of reactive microglia from hTau-Cx3cr1 –/– mice led to induction of tau hyperphosphorylation and aggregation within the brains of recipient mice, which was also mediated via the IL-1β–p38α MAPK signaling pathway [23].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015;138(Pt 6):1738–55. source

      The Discussion reports that transferred hTauCx3cr1−/− microglia induced tau phosphorylation and ‘pre-tangle-type’ aggregation in recipient brains. The Results show that an IL-1 receptor antagonist reduced tau hyperphosphorylation and p38 MAPK activation, supporting the proposed pathway. The paper does not identify the p38α isoform specifically or establish that this pathway mediates the aggregation finding. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Interpretationcitation

    The recent description of a drug candidate that retains all of the positive attributes of MW181, but is further optimized for bioavailability and in-vivo safety, provides the means to extend the rationale presented here for tauopathies toward clinical proof of concept.

    “The recent description [25] of a drug candidate that retains all of the positive attributes of MW181, but is further optimized for bioavailability and in-vivo safety, provides the means to extend the rationale presented here for tauopathies toward clinical proof of concept.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Roy SM, Grum-Tokars VL, Schavocky JP, Saeed F, Staniszewski A, Teich AF, Arancio O, Bachstetter AD, Webster SJ, Van Eldik LJ, et al. Targeting human central nervous system protein kinases: An isoform selective p38alphaMAPK inhibitor that attenuates disease progression in Alzheimer’s disease mouse models. ACS Chem Neurosci. 2015;6(4):666–80. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    There was no significant effect of either LPS or MK2 deficiency on PHF1 site tau phosphorylation.

    “There was also no significant effect of either LPS or MK2 deficiency on PHF1 site tau phosphorylation (Fig. 4b, e).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SB239063 induced a modest increase in synaptophysin levels; however, the difference versus vehicle control was not statistically significant when analyzed with multiple comparisons via one-way ANOVA.

    “SB239063 induced a modest increase in synaptophysin levels; however, the difference (versus vehicle control) was not statistically significant when analyzed with multiple comparisons via one-way ANOVA (Fig. 3a, e).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Inhibition of p38α MAPK by MW181, but not by SB239063, led to a significant decrease in both IFNγ and IL-1β expression in the 20-month-old hTau mice.

    “Inhibition of p38α MAPK by MW181, but not by SB239063, led to a significant decrease in both IFNγ and IL-1β expression in the 20-month-old hTau mice (Fig. 3f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Quantitative morphometric scoring showed a statistically significant decrease in AT180+ neurons in MW181-treated but not in SB239063-treated hTau mice.

    “Interestingly, quantitative morphometric scoring of the percentage of AT180+ area in two different fields covering CA3/DG with three sections per mouse and from three mice per group showed a statistically significant decrease in AT180+ neurons in MW181-treated but not in SB239063-treated hTau mice (Fig. 2e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SB239063 showed a biphasic effect with an initial drop in p-p38α MAPK and AT8 site tau phosphorylation at 20 min and then again at 60 min after CM treatment, with a sharp spike at 40 min.

    “In contrast to MW181, SB239063 showed a biphasic effect with an initial drop in the p-p38α MAPK and AT8 site tau phosphorylation at 20 min and then again at 60 min after Cx3cr1 –/– CM treatment (Fig. 1g, i).”
    • Also stated in: § MW181 and SB239063 treatment rescued inflammation-induced phosphorylation of tau, p38α MAPK, and ATF2 in primary neurons · plain
      “There was a sharp spike in both p38α MAPK and AT8 site tau phosphorylation at the 40-min time point (Fig. 1g, i).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Upon quantification, there was a statistically significant reduction in the Iba1 immunoreactivity and the number of CX3CR1+ activated microglial cells, but not in the CD3+ T cells/B220+ B cells, in MW181-treated or SB239063-treated groups compared with vehicle-treated 20-month-old hTau mice.

    “Upon quantification, we observed statistically significant reduction in the Iba1 immunoreactivity and the number of CX3CR1+ activated microglial cells, but not in the CD3+ T cells/B220+ B cells, in MW181-treated or SB239063-treated groups compared with vehicle-treated 20-month-old hTau mice (Fig. 3h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The difference in the Sarkosyl-insoluble/soluble ratios for AT8 showed statistically significant reduction only with MW181, but not with SB239063 treatment, compared with vehicle.

    “Because of the variability, the difference in the Sarkosyl insoluble/soluble ratios for AT8 showed statistically significant reduction only with MW181, but not with SB239063 treatment, compared with vehicle (Fig. 2g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both IL-6 and TNFα levels displayed marginal reduction with MW181 treatment, but the differences were not statistically significant.

    “Interestingly, both IL-6 and TNFα levels also displayed marginal reduction with MW181 treatment during this same time. However, the differences were not statistically significant (Fig. 3f).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Immunohistochemical and immunofluorescence analysis shows Iba1+ microglia and CD45+ microglia/macrophages in the CA3 region of hippocampus, B220+ B cells and CD3+ T cells in the meninges, and CX3CR1+ microglia in the CA3 region of the hippocampus in MW181-treated, Veh-treated, or SB239063-treated 20-month-old hTau mice.

    “Immunohistochemical and immunofluorescence analysis shows Iba1+ microglia and CD45+ microglia/macrophages in the CA3 region of hippocampus, B220+ B cells and CD3+ T cells in the meninges, and CX3CR1+ microglia in the CA3 region of the hippocampus in MW181-treated, Veh-treated, or SB239063-treated 20-month-old hTau mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    p38α MAPK inhibition by MW181 leads to both MK2 deactivation and reduced tau phosphorylation.

    “Since p38α MAPK inhibition by MW181 leads to both MK2 deactivation and reduced tau phosphorylation (Fig. 3), we tested whether MK2 deficiency would prevent LPS-induced tau phosphorylation in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    B220 and CD3 showed a reduced trend in MW181-treated groups but were not statistically significant, unlike Iba1 and CX3CR1 which were significant.

    “Note that B220 and CD3 showed a reduced trend in MW181-treated groups but were not statistically significant, unlike Iba1 and CX3CR1 which were significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    MW181-treated aged hTau mice showed a significant reduction in both pATF2 and pMK2 compared with vehicle-treated groups.

    “MW181-treated aged hTau mice showed a significant reduction in both pATF2 and pMK2 compared with vehicle-treated groups (Fig. 3a, c, d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    We observed no alterations in the levels of pT180/pY182 in p38α MAPK in vivo but we did in vitro.

    “Indeed, this is the reason why we observed no alterations in the levels of pT180/pY182 in p38α MAPK in vivo but we did in vitro (Figs. 1 and 3).”
    Quote in the paperSubstantial claim

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

    Premisereasoning

    Tau can contribute to the disease process either via loss of function or gain of toxic function.

    “Based on these studies, the current consensus in the field is that tau can contribute to the disease process either via loss of function (e.g., failure to bind to microtubules) or gain of toxic function (e.g., by affecting various types of non-microtubule binding functions).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    These inhibitors vary in their target specificity, which raises concerns about linkage of target modulation to phenotype.

    “These inhibitors vary in their target specificity, which raises concerns about linkage of target modulation to phenotype—a key aspect of drug discovery target validation, as documented previously [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Laco F, Low JL, Seow J, Woo TL, Zhong Q, Seayad J, Liu Z, Wei H, Reuveny S, Elliott DA, et al. Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling. J Mol Cell Cardiol. 2015;80:56–70. source

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

    Study design and conductnone given

    Slides were coded prior to scoring and analysis was performed in a blinded manner.

    “Slides were coded prior to scoring and the analysis was performed in a blinded manner.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    MW181 may prevent cognitive impairment in aged hTau mice, possibly attributed to increasing synaptophysin levels.

    “We also show that MW181 may prevent cognitive impairment in the aged hTau mice, possibly attributed to increasing synaptophysin levels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductnone given

    All in vitro experiments were performed in triplicate with independent cultures.

    “All experiments were performed in triplicate with independent cultures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    MW181 can significantly affect the in-vivo catalytic activity of p38α MAPK with a resultant reduction in the site-specific phosphorylation of known substrates (T71 and T334 sites in ATF2 and MK2, respectively).

    “These results indicate that MW181 can significantly affect the in-vivo catalytic activity of p38α MAPK with a resultant reduction in the site-specific phosphorylation of known substrates (T71 and T334 sites in ATF2 and MK2, respectively).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Quantitative morphometric scoring was performed by an individual blinded to treatment/genotype.

    “Three different fields (covering the dorsolateral hippocampal area) per section and three random sections per mouse brain were scored by an individual blinded to the treatment/genotype.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    All animals receiving treatment were monitored for weight loss/gain, grooming changes and posture over 14 days; no differences were noted.

    “All animals receiving treatment were monitored for weight loss/gain, grooming changes and posture over 14 days; no differences were noted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Primarily MW181, but to a lesser extent SB239063, are both capable of suppressing proinflammatory responses, while inducing alternative, more neuroprotective, anti-inflammatory responses in the brain.

    “Together, these results suggest that primarily MW181, but to a lesser extent SB239063, are both capable of suppressing proinflammatory responses, while inducing alternative, more neuroprotective, anti-inflammatory responses in the brain.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The Y-maze was used to evaluate spatial working memory.

    “A symmetrical Y maze was used to evaluate spatial working memory [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Hughes RN. The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev. 2004;28(5):497–505. source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Targeting the p38α MAPK signaling pathway should be tested as a potential strategy to suppress microglial innate immune responses and prevent inflammation-mediated tau pathology.

    “These studies suggest that targeting the p38α MAPK signaling pathway should be tested as a potential strategy to suppress microglial innate immune responses and prevent inflammation-mediated tau pathology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    SB239063 and MW181 could reduce tau hyperphosphorylation and aggregation as well as improve working memory in 20-month-old hTau mice.

    “Together, these results suggest that SB239063 and MW181 could reduce tau hyperphosphorylation and aggregation as well as improve working memory in 20-month-old hTau mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These results identify p38α MAPK as a druggable target that can block inflammation-induced tau pathology and improve cognitive function in tauopathies.

    “These results identify p38α MAPK as a druggable target that can block inflammation-induced tau pathology and improve cognitive function in tauopathies.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Reduced LPS-induced tau phosphorylation in MK2 deficient mice is due to the feed-forward abrogation of the MK2 > IL-1β > IL-1R > p38α MAPK > tau axis.

    “Therefore, based on current evidence, it is conceivable that reduced LPS-induced tau phosphorylation in MK2 deficient mice is due to the feed-forward abrogation of the MK2 > IL-1β > IL-1R > p38α MAPK > tau axis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    This report provides the most conclusive demonstration that selective inhibition of p38α MAPK alone can significantly reduce Sarkosyl-insoluble NFTs, increase synaptophysin, and reduce the expression of proinflammatory cytokines in a pure tauopathy model with advanced stages of disease.

    “To our knowledge, this report provides the most conclusive demonstration that selective inhibition of p38α MAPK alone can significantly reduce Sarkosyl-insoluble NFTs, increase synaptophysin, and reduce the expression of proinflammatory cytokines in a pure tauopathy model with advanced stages of disease.”
    Quote in the paperSubstantial claim
38 of 38

  • The paper relies on this without support.

    Hyperphosphorylation and aggregation of tau protein are pathological hallmarks of Alzheimer’s disease and related tauopathies.

    “Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies.”

  • The paper relies on this without support.

    MW181 is brain-permeable and orally bioavailable.

    “We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice.”

  • The paper relies on this without support.

    Activation of both ATF2 and MK2 may lead to the expression of various proinflammatory cytokines/chemokines including IL-1β.

    “Activation of both ATF2 and MK2 may lead to the expression of various proinflammatory cytokines/chemokines including IL-1β.”

  • The paper relies on this without support.

    IFNγ is primarily secreted by T cells.

    “IFNγ is primarily secreted by T cells”

  • The paper relies on this without support.

    IL-1β is one of the key proinflammatory cytokines important for LPS-induced p38α MAPK activation.

    “IL-1β is one of the key proinflammatory cytokines important for LPS-induced p38α MAPK activation”
5 of 5

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?

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.

  • Abstract claims significant in-vivo p38α MAPK reduction, but results report none

    Major

    The abstract says MW181 significantly reduced p38α MAPK activation in old hTau mice. The in-vivo results instead say the phosphorylated-to-total p38α MAPK level did not significantly decrease with MW181.

  • MK2 antibody phosphorylation site differs between methods and results

    Minor

    The methods identify the phosphorylated MK2 antibody as targeting pT233, whereas the results identify the measured phosphorylated MK2 site as pT334.

  • AT180 morphometry field count differs between methods and figure legend

    Minor

    The morphometry methods say three fields were scored per section, while the Fig. 2 AT180 morphometry legend says two fields were quantified per section.

3 of 3

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Related

Authors
Maphis, N., Jiang, S., Xu, G., Kokiko-Cochran, O. N., Roy, S. M., Van Eldik, L. J., Watterson, D. M., Lamb, B. T., & Bhaskar, K.
Affiliations
  • University of New Mexico (US)
  • Indiana University Indianapolis (US)
  • Northwestern University (US)
Corresponding author
Bhaskar, Kiran
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2016-12
Volume
8
Issue
1
Pages
54-54
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-016-0221-y
PMC
PMC5157054
OpenAlex
W2558063058
Cited by
144
References
70
Citations by year
2026: 10 · 2025: 15 · 2024: 14 · 2023: 13 · 2022: 17 · 2021: 24 · 2020: 15 · 2019: 14 · 2018: 12 · 2017: 9
FWCI
8.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
  • PMC
Funders
  • BrightFocus Foundation (AHAF0311KB)
  • National Institute of Neurological Disorders and Stroke (NS074804, NS093920)
  • Alzheimer's Association (NIRG-11-204995)
  • U.S. Department of Defense (ERMS#12109018)
  • National Institute on Aging (AG023012)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
p38 MAPK, tau hyperphosphorylation, tauopathy, Alzheimer's disease, microglial activation, CX3CR1, small molecule inhibitors, MAPKAPK2
MeSH terms
MAP-Kinase-Activated Kinase 2, Animals, Behavior, Animal, Cerebral Cortex, Disease Models, Animal, Interferon-gamma, Memory, Short-Term, Mice, Inbred C57BL, Neurons

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 2026-10-18.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-18.

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