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Cited by 516Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation

Open access
Chen, Yijun, Yu, Yang·2023·Journal of Neuroinflammation
DOI 10.1186/s12974-023-02853-3PMC PMC10349496
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Abstract

Alzheimer’s Disease (AD) contributes to most cases of dementia. Its prominent neuropathological features are the extracellular neuritic plaques and intercellular neurofibrillary tangles composed of aggregated β-amyloid (Aβ) and hyperphosphorylated tau protein, respectively. In the past few decades, disease-modifying therapy targeting Aβ has been the focus of AD drug development. Even though it is encouraging that two of these drugs have recently received accelerated US Food and Drug Administration approval for AD treatment, their efficacy or long-term safety is controversial. Tau has received increasing attention as a potential therapeutic target, since evidence indicates that tau pathology is more associated with cognitive dysfunction. Moreover, inflammation, especially neuroinflammation, accompanies AD pathological processes and is also linked to cognitive deficits. Accumulating evidence indicates that inflammation has a complex and tight interplay with tau pathology. Here, we review recent evidence on the interaction between tau pathology, focusing on tau post-translational modification and dissemination, and neuroinflammatory responses, including glial cell activation and inflammatory signaling pathways. Then, we summarize the latest clinical trials targeting tau and neuroinflammation. Sustained and increased inflammatory responses in glial cells and neurons are pivotal cellular drivers and regulators of the exacerbation of tau pathology, which further contributes to its worsening by aggravating inflammatory responses. Unraveling the precise mechanisms underlying the relationship between tau pathology and neuroinflammation will provide new insights into the discovery and clinical translation of therapeutic targets for AD and other tau-related diseases (tauopathies). Targeting multiple pathologies and precision therapy strategies will be the crucial direction for developing drugs for AD and other tauopathies.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that tau pathology and neuroinflammation are tightly intertwined in Alzheimer’s disease, with sustained glial and neuronal inflammatory responses exacerbating tau post-translational modification and propagation in a vicious cycle. It summarizes tau- and neuroinflammation-targeted drug candidates in clinical trials and concludes that multi-target and precision therapies are likely needed for AD and other tauopathies.

Key findings

  • Tau pathology correlates more closely with cognitive dysfunction than Aβ, and soluble oligomeric tau—not only insoluble fibrils/NFTs—is proposed to play a critical role in neurotoxicity and propagation. In AD brain, tau is reported to be twofold to threefold hyperphosphorylated versus 2–3 mol phosphate per mole tau in normal adult brain.
  • Neuroinflammation is described as a third core AD pathological feature. Microglia and astrocytes can exacerbate tau hyperphosphorylation and spreading via receptors and pathways including TREM2, CX3CR1/CX3CL1, FPR2, CMKLR1, NLRP3/IL-1β/p38α MAPK, NF-κB, and exosome-mediated tau propagation.
  • The review reports that as of January 2022, among 143 drugs in the AD pipeline, 83.2% were disease-modifying; 20 (16.8%) targeted Aβ, 13 (10.9%) tau, 28 (19.3%) inflammation, and 19 (16%) synaptic plasticity or neuroprotection. More than 50 inflammation-related agents have entered AD trials, with 22 currently ongoing, and 12 tau antibodies have entered clinical trials, half terminated for poor efficacy.
  • Clinical translation remains mixed: anti-tau vaccines and antibodies have largely failed to show cognitive benefit, while some p38α inhibitors, nilotinib, NE3107, senolytics, and GV-971 show biomarker, safety, or cognitive signals that require further validation.

Methods

  • Narrative review of recent evidence on tau pathology and neuroinflammation in AD, focusing on tau post-translational modification, tau dissemination, glial activation, and inflammatory signaling pathways.
  • Summarizes clinical trials targeting tau and neuroinflammation, with a representative table of drug candidates compiled from ClinicalTrials.gov and Alzforum, accessed March 2023.
  • No systematic review, meta-analysis, or primary experimental data are reported.

Limitations

  • The paper does not state explicit limitations.
  • Evident from the text: it is a narrative review without a systematic search strategy or formal quality assessment.
  • The clinical trial table is current only to March 2023, and many listed trials are ongoing, terminated, suspended, or have unknown/no reported results, so efficacy and safety conclusions are provisional.

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

Integrity signals

Registry

Crossref · 10.1186/s12974-023-02853-3

Cites

261 of 261 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 255 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    AD is considered a secondary tauopathy because tau pathology may occur as a consequence of extracellular amyloid plaques.

    “AD is considered a secondary tauopathy due to tau pathology may occur as a consequence of extracellular amyloid plaques.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Götz J, Halliday G, Nisbet RM. Molecular pathogenesis of the tauopathies. Annu Rev Pathol. 2019;14:239–61. source

      Not checked in the free run.

  • Interpretationcitation

    Soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau, including NFTs.

    “These findings indicate that soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau (including NFT), the “tau we can see”.”
    Quote in the paperSubstantial claim0 of 7 sources checked
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      Not checked in the free run.

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  • Interpretationnone given

    Inflammation has a complex and tight interplay with tau pathology.

    “Accumulating evidence indicates that inflammation has a complex and tight interplay with tau pathology.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In AD brains, tau aggregates into NFTs or neuropil threads composed of 3R and 4R tau.

    “In AD brains, tau aggregates into NFTs or neuropil threads composed of 3R and 4R Tau [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Götz J, Halliday G, Nisbet RM. Molecular pathogenesis of the tauopathies. Annu Rev Pathol. 2019;14:239–61. source

      Not checked in the free run.

  • Premisecitation

    Activation of inflammatory processes and immune responses are commonly observed in AD brain tissues.

    “In addition, activation of inflammatory processes and immune responses are commonly observed in AD brain tissues [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Leng FD, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17:157–72. source

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  • Classified as probably not a substantial claim. 7

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    Premisecitation

    Mutations in the MAPT gene lead to FTDP-17, providing evidence that tau dysfunction due to tau mutations induces neurodegeneration.

    “Mutations in the MAPT gene lead to FTDP-17 [22], providing evidence that tau dysfunction due to tau mutations induces neurodegeneration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, et al. Association of missense and 5 ’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702–5. source

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

    Premisecitation

    Lecanemab was approved by the FDA in January 2023 for early AD via accelerated approval.

    “In January 2023, FDA approved a new monoclonal antibody against Aβ called lecanemab for the treatment of early AD, also by its accelerated approval pathway.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21. source

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    Premisecitation

    Inhibition of endogenous tau improves behaviors and protects neurons from toxicity in APP/PS1 mice.

    “Furthermore, inhibition of endogenous tau improves behaviors and protects neurons from toxicity in APP/PS1 mice, a mouse model with AD-like Aβ pathology [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Wegmann S, DeVos SL, Zeitler B, Marlen K, Bennett RE, Perez-Rando M, MacKenzie D, Yu Q, Commins C, Bannon RN, et al. Persistent repression of tau in the brain using engineered zinc finger protein transcription factors. Sci Adv. 2021. https://doi.org/10.1126/sciadv.abe1611. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammation, especially neuroinflammation, accompanies AD pathological processes and is linked to cognitive deficits.

    “Moreover, inflammation, especially neuroinflammation, accompanies AD pathological processes and is also linked to cognitive deficits.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Bettcher BM, Tansey MG, Dorothee G, Heneka MT. Peripheral and central immune system crosstalk in Alzheimer disease—a research prospectus. Nat Rev Neurol. 2021;17:689–701. source

      Not checked in the free run.

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    Premisecitation

    Inflammatory responses, especially neuroinflammation, accompany the entire progress of AD pathogenesis and are linked to cognitive dysfunction.

    “The inflammatory responses (especially neuroinflammation) accompany the entire progress of AD pathogenesis and are also linked to cognitive dysfunction [15].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Bettcher BM, Tansey MG, Dorothee G, Heneka MT. Peripheral and central immune system crosstalk in Alzheimer disease—a research prospectus. Nat Rev Neurol. 2021;17:689–701. source

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

    Interpretationreasoning

    The efficacy or long-term safety of aducanumab and lecanemab needs further validation.

    “The efficacy or long-term safety of these two drugs needs further validation.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Aducanumab became the first disease-modifying therapy drug for AD approved by the FDA's accelerated pathway.

    “It is encouraging that in 2021, aducanumab, a humanized recombinant monoclonal antibody targeting Aβ, became the first disease-modifying therapy (DMT) drug for AD approved by an accelerated pathway of the US Food and Drug Administration (FDA).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Kantarci K. 2021 marks a new era for Alzheimer’s therapeutics. Lancet Neurol. 2022;21:3–4. source

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    • cites [9] Mullard A. FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm. Nat Rev Drug Discov. 2021;20:496–496.

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    Premisecitation

    Two anti-Aβ drugs have received accelerated FDA approval for AD treatment, but their efficacy or long-term safety is controversial.

    “Even though it is encouraging that two of these drugs have recently received accelerated US Food and Drug Administration approval for AD treatment, their efficacy or long-term safety is controversial.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Kantarci K. 2021 marks a new era for Alzheimer’s therapeutics. Lancet Neurol. 2022;21:3–4. source

      Not checked in the free run.

    • cites [9] Mullard A. FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm. Nat Rev Drug Discov. 2021;20:496–496.

      Not checked in the free run.

    • cites [10] van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lecanemab reduced brain amyloid burden markedly and cognitive decline moderately compared with placebo at 18 months in early AD, but was related to adverse events.

    “Lecanemab reduced brain amyloid burden markedly in early AD and cognitive decline moderately than placebo at 18 months but was related to adverse events [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau pathology is more associated with cognitive dysfunction than Aβ pathology, making tau a potential therapeutic target.

    “Tau has received increasing attention as a potential therapeutic target, since evidence indicates that tau pathology is more associated with cognitive dysfunction.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42:631–631. source

      Not checked in the free run.

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    Premisecitation

    Pathogenic tau can be released from diseased neurons, taken up by previously unaffected normal neurons, and induce pathogenic tau production in normal neurons.

    “The pathogenic tau can be released from diseased neurons, then uptake by previously unaffected normal neurons, inducing pathogenic tau production in normal neurons.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

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    Premisecitation

    Tau propagation-induced tau pathology is based on the spread of tau between neurons and the dissemination between neurons and glial cells.

    “Furthermore, tau propagation-induced tau pathology is based on the spread of tau between neurons and the dissemination between neurons and glial cells [81, 82].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li AM, Barker SJ, Foley AC, Thorpe JR, Serpell LC, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82:1271–88. source

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  • May combine two claims.

    Premisecitation

    Exosomes carrying tau are taken up by local and remote cells and contribute to apoptosis and neuronal loss.

    “Exosomes carrying tau are taken up by local and remote cells and contribute to apoptosis and neuronal loss [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Agosta F, Dalla Libera D, Spinelli EG, Finardi A, Canu E, Bergami A, Chiavetto LB, Baronio M, Comi G, Martino G, et al. Myeloid microvesicles in cerebrospinal fluid are associated with myelin damage and neuronal loss in mild cognitive impairment and alzheimer disease. Ann Neurol. 2014;76:813–25. source

      Not checked in the free run.

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    Premisecitation

    Acetylation of tau is an early pathological feature of neurodegeneration; acetylated tau inhibits its degradation, promotes pathological aggregation and propagation, and contributes to tauopathy.

    “In addition, the acetylation of tau is an early pathological feature of neurodegeneration. Acetylated tau inhibits its degradation, promotes pathological aggregation and propagation, and contributes to tauopathy [46–51].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
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    Premisecitation

    The spread of tau pathology in AD follows a predictable pattern, allowing neuropathological diagnosis of different AD stages defined by Braak staging (I-VI).

    “Postmortem studies have shown that the spread of tau pathology in AD follows a predictable pattern, allowing neuropathological diagnosis of different AD stages defined by Braak staging (I–VI).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    C-terminal truncated tau is abundant in cortical pre-synaptic terminals, and tau cleavage promotes tau aggregation, secretion, and propagation in AD.

    “Sokolow et al. revealed that C-terminal truncated tau is abundant in the cortical pre-synaptic terminals, and tau cleavage promotes tau aggregation, secretion, and propagation in AD [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Increased neuronal activity enhances the release of tau-containing exosomes and exacerbates tau propagation and pathology.

    “Increased neuronal activity enhances the release of tau-containing exosomes [75] and exacerbates tau propagation and pathology [78].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Under pathological conditions, hyperphosphorylation destabilizes tau interaction with microtubules and enhances tau accumulation in the cytoplasm, leading to microtubule instability and transport dysfunction.

    “However, under pathological conditions, various highly increased post-translational modifications, such as hyperphosphorylation, destabilize the interaction of tau with microtubules [33] and enhance the capacity of tau to accumulate in the cytoplasm [34], leading to microtubule instability and transport dysfunction.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Abnormally hyperphosphorylated or oligomeric tau can be secreted from neurons into the extracellular space, taken up by other normal neurons, and cause interneuronal transfer of tau pathology and spreading of tau toxicity across different brain regions.

    “there is a large amount of evidence indicating that the abnormally hyperphosphorylated or oligomeric tau can be secreted from neurons into the extracellular space, then be taken up by other normal neurons, and finally causes interneuronal transfer of tau pathology and spreading of tau toxicity across different brain regions [59–61]”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    Premisecitation

    Trans-synaptic tau propagation and aggregation can be independent of endogenous soluble tau, but the absence of endogenous tau reduces its neurotoxicity.

    “In addition, trans-synaptic tau propagation and aggregation can also be independent of the presence of endogenous soluble tau, but the absence of endogenous tau reduces its neurotoxicity [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Hyperphosphorylated tau leads to abnormal aggregation of tau protein, which loses its ability to stabilize microtubules, thereby impairing neuronal function.

    “Hyperphosphorylated tau leads to abnormal aggregation of tau protein, which loses its ability to stabilize microtubules, thereby impairing neuronal function [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Reduced tau O-glycosylation could lead to increased phosphorylation, while enhancement of O-glycosylation reduces the extent of tau phosphorylation.

    “For example, reduced tau O-glycosylation could lead to increased phosphorylation, while the enhancement of O-glycosylation reduces the extent of tau phosphorylation [43–45].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Premisecitation

    Glial cells such as microglia and astrocytes perform normal immune functions in the CNS and play a vital role in the spreading of pathological tau.

    “Glial cells such as microglia and astrocytes perform normal immune functions in CNS and also play a vital role in the spreading of pathological tau [80, 83].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Pathological activation of glial cells and release of inflammatory factors involved in neuroinflammation can exacerbate tau pathology via direct or indirect pathways, leading to neuronal damage and cognitive impairment, ultimately aggravating AD pathology.

    “Evidence suggests that the pathological activation of glial cells and the release of inflammatory factors involved in neuroinflammation can exacerbate tau pathology via direct or indirect pathways, leading to neuronal damage and cognitive impairment, ultimately aggravating AD pathology [113, 114].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [113] Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer’s disease model. J Immunol. 2011;187:6539–49. source

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    • cites [114] Leyns CEG, Holtzman DM. Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener. 2017;12:50. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The immune response exists throughout the pathological progress of AD, suggesting that it may also participate in and aggravate disease development.

    “Furthermore, since the immune response exists throughout the pathological progress of AD [104, 105], suggesting that it may also participate in and aggravate the disease development.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [104] Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. source

      Not checked in the free run.

    • cites [105] Blasko I, Grubeck-Loebenstein B. Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer’s disease. Drugs Aging. 2003;20:101–13. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In tau-P301S transgenic mice, TREM2 deletion attenuates neuroinflammation and protects against neurodegeneration at a late stage without altering tau phosphorylation and aggregation.

    “In contrast, in tau-P301S transgenic mice, TREM2 deletion attenuates neuroinflammation and protects against neurodegeneration at a late stage without altering tau phosphorylation and aggregation [127].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Leyns CEG, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, Robinson GO, Anderson E, Colonna M, Holtzman DM. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017;114:11524–9. source

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  • May combine two claims.

    Premisecitation

    The link between neuroinflammation and AD was discovered decades ago, but it remains unclear whether it is a cause or a consequence of the disease.

    “Although the link between neuroinflammation and AD was discovered decades ago [102], it remains unclear whether it is a cause or a consequence of the disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] McGeer PL, Rogers J, McGeer EG. Inflammation, antiinflammatory agents, and Alzheimer’s disease: the last 22 years. J Alzheimers Dis. 2016;54:853–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upregulation of proinflammatory cytokines has been observed even before signs of increased Aβ and hyperphosphorylated tau in CSF of MCI patients, suggesting that inflammatory processes occur in the early stages of AD.

    “Interestingly, the upregulation of such proinflammatory cytokine has been observed even before signs of increased Aβ and hyperphosphorylated tau in CSF of mild cognitive impairment (MCI) patients [101], suggesting that the inflammatory processes had occurred in the early stages of AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Schuitemaker A, Dik MG, Veerhuis R, Scheltens P, Schoonenboom NSM, Hack CE, Blankenstein MA, Jonker C. Inflammatory markers in AD and MCI patients with different biomarker profiles. Neurobiol Aging. 2009;30:1885–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic neuroinflammation is caused by persistent activation of glial cells and excessive release of cytotoxic molecules, adversely affects brain function, and is a major cofactor in the pathogenesis of many neurodegenerative disorders including AD.

    “This chronic neuroinflammation is caused by persistent activation of glial cells and excessive release of cytotoxic molecules, which adversely affects brain function and is a major cofactor in the pathogenesis of many neurodegenerative disorders, including AD [84].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (NY). 2018;4:575–90. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments.

    “Deletion of CX3CR1 or depression of the CX3CL1/CX3CR1 axis reduces Aβ deposition [130–132] but exacerbates tau pathology, such as increased phosphorylation and aggregation of tau, and this is associated with worsened behavioral and cognitive impairments [132–137] (Fig. 1).”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [130] Liu Z, Condello C, Schain A, Harb R, Grutzendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J Neurosci. 2010;30:17091–101. source

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    • cites [131] Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol. 2010;177:2549–62. source

      Not checked in the free run.

    • cites [132] Puntambekar SS, Moutinho M, Lin PBC, Jadhav V, Tumbleson-Brink D, Balaji A, Benito MA, Xu GX, Oblak A, Lasagna-Reeves CA, et al. CX3CR1 deficiency aggravates amyloid driven neuronal pathology and cognitive decline in Alzheimer’s disease. Mol Neurodegener. 2022;17:21. source

      Not checked in the free run.

    • cites [133] Lee S, Xu G, Jay TR, Bhatta S, Kim KW, Jung S, Landreth GE, Ransohoff RM, Lamb BT. Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. J Neurosci. 2014;34:12538–46. source

      Not checked in the free run.

    • cites [134] Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM, Kretzschmar H, Herms J. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci. 2010;13:411–3. source

      Not checked in the free run.

    • cites [135] 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;138:1738–55. source

      Not checked in the free run.

    • cites [136] Fan Q, He W, Gayen M, Benoit MR, Luo X, Hu X, Yan R. Activated CX3CL1/Smad2 signals prevent neuronal loss and alzheimer’s tau pathology-mediated cognitive dysfunction. J Neurosci. 2020;40:1133–44. source

      Not checked in the free run.

    • cites [137] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of Tau Pathology by the Microglial Fractalkine Receptor. Neuron. 2010;68:19–31. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cell-to-cell spreading of abnormal tau plays a pivotal role in neurotoxicity and provides potential therapeutic strategies for tau-targeted immunotherapies in AD and other tauopathies.

    “These findings reveal a pivotal role in the cell-to-cell spreading of abnormal tau in neurotoxicity and provide potential therapeutic strategies for tau-targeted immunotherapies in AD and other tauopathies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the CSF of AD patients, the R47H variant of TREM2 or soluble TREM2 correlates with total or phosphorylated tau (Thr181), respectively, but not with Aβ42.

    “In the CSF of AD patients, the R47H (rs75932628) variant of TREM2 or soluble TREM2 has been found to correlate with total or phosphorylated tau (Thr181), respectively, but not with Aβ42 [124, 125].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [124] Lill CM, Rengmark A, Pihlstrom L, Fogh I, Shatunov A, Sleiman PM, Wang LS, Liu T, Lassen CF, Meissner E, et al. The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimers Dement. 2015;11:1407–16. source

      Not checked in the free run.

    • cites [125] Piccio L, Deming Y, Del-Aguila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016;131:925–33. source

      Not checked in the free run.

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

    Premisecitation

    Astrocytes are the most abundant glial cells in the brain and have complex essential functions in the CNS, including maintenance of brain homeostasis, synaptic transmission, and information processing through neural circuits.

    “Astrocytes are the most abundant glial cells in the brain and have a variety of complex and essential functions in CNS, including maintenance of brain homeostasis, synaptic transmission, and information processing through neural circuits [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 is a pivotal risk factor for LOAD and is associated with tau pathology.

    “TREM2, a pivotal risk factor for LOAD [119, 120], is associated with tau pathology.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [119] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368:107–16. source

      Not checked in the free run.

    • cites [120] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368:117–27. source

      Not checked in the free run.

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

    Premisecitation

    Microglia are the resident immune cells of the brain and play a pivotal role in the immune defense of the CNS.

    “Microglia are the resident immune cells of the brain and play a pivotal role in the immune defense of CNS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Astrocytes become activated in AD and exhibit certain immune functions.

    “Astrocytes become activated in AD and exhibit certain immune functions.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [95] Carrero I, Gonzalo MR, Martin B, Sanz-Anquela JM, Arevalo-Serrano J, Gonzalo-Ruiz A. Oligomers of beta-amyloid protein (A beta 1–42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain. Exp Neurol. 2012;236:215–27. source

      Not checked in the free run.

    • cites [96] Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. Astrocytes are important mediators of Abeta-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis. 2011;2: e167. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic administration of LPS leads to microglial activation in the mouse brain, which results in tau hyperphosphorylation at specific sites.

    “Our and other studies found that systemic administration of lipopolysaccharide (LPS, inducer of inflammation) leads to microglial activation in the mouse brain, which results in tau hyperphosphorylation at specific sites [117, 118].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Liu J, Wang D, Li SQ, Yu Y, Ye RD. Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A. J Neuroinflammation. 2016;13:15. source

      Not checked in the free run.

    • cites [118] Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci. 2005;25:8843–53. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deficiency of FPR2 or administration of its inhibitors/anti-inflammatory ligands alleviates pathological symptoms of AD, including reduced activation of glial cells and tau hyperphosphorylation, and ultimately improves cognitive function.

    “Deficiency of FPR2 or administration of its inhibitors/anti-inflammatory ligands could alleviate the pathological symptoms of AD, including reduced activation of glial cells (microglia and/or astrocytes) and tau hyperphosphorylation, and ultimately leading to improvement in cognitive function [151–154].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [151] Medeiros R, Kitazawa M, Passos GF, Baglietto-Vargas D, Cheng D, Cribbs DH, LaFerla FM. Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice. Am J Pathol. 2013;182:1780–9. source

      Not checked in the free run.

    • cites [152] Zhang H, Wang D, Gong P, Lin A, Zhang Y, Ye RD, Yu Y. Formyl peptide receptor 2 deficiency improves cognition and attenuates tau hyperphosphorylation and astrogliosis in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2019;67:169–79. source

      Not checked in the free run.

    • cites [153] Schroder N, Schaffrath A, Welter JA, Putzka T, Griep A, Ziegler P, Brandt E, Samer S, Heneka MT, Kaddatz H, et al. Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease. J Neuroinflammation. 2020;17:131. source

      Not checked in the free run.

    • cites [154] Trojan E, Tylek K, Schroder N, Kahl I, Brandenburg LO, Mastromarino M, Leopoldo M, Basta-Kaim A, Lacivita E. The N-formyl peptide receptor 2 (FPR2) agonist MR-39 improves ex vivo and in vivo amyloid beta (1–42)-induced neuroinflammation in mouse models of Alzheimer’s disease. Mol Neurobiol. 2021;58:6203–21. source

      Not checked in the free run.

    • Rests on an assumption: Findings from transgenic mouse models of tau pathology and neuroinflammation are representative of human AD and can guide therapeutic development.

  • May combine two claims.

    Premisecitation

    The R47H variant of TREM2 presents an altered glycosylation pattern and decreased stability compared with wild-type TREM2.

    “Interestingly, the R47H variant of TREM2, which is expressed by microglia and linked to innate immunity, has been found to present an altered glycosylation pattern and decreased stability compared with wild-type TREM2 [176], indicating a potential link between microglial neuroinflammation and glycosylation [177, 178].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [176] Park JS, Ji IJ, Kim DH, An HJ, Yoon SY. The Alzheimer’s disease-associated R47H variant of TREM2 has an altered glycosylation pattern and protein stability. Front Neurosci. 2016;10:618.

      Not checked in the free run.

    • cites [177] Haukedal H, Freude KK. Implications of glycosylation in Alzheimer’s disease. Front Neurosci. 2021;14:18. source

      Not checked in the free run.

    • cites [178] Rebelo AL, Chevalier MT, Russo L, Pandit A. Role and therapeutic implications of protein glycosylation in neuroinflammation. Trends Mol Med. 2022;28:270–89. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increases in tau O-GlcNAcylation inhibit tau aggregates and neuronal cell loss.

    “Increases in tau O-GlcNAcylation inhibit tau aggregates and neuronal cell loss [174], indicating that O-GlcNAcylation modification can protect AD progression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012;8:393–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of SAA by intracerebral injection attenuates tau hyperphosphorylation, and the mechanism is related to SAA-induced secretion of IL-10 from microglia.

    “Overexpression of SAA by intracerebral injection attenuates tau hyperphosphorylation, and the mechanism is related to SAA-induced secretion of IL-10 from microglia [117].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Liu J, Wang D, Li SQ, Yu Y, Ye RD. Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A. J Neuroinflammation. 2016;13:15. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The expression and activity of p300 are increased in the brain of AD patients, and dysregulation of p300/CBP promotes tau acetylation, which could aggravate tau accumulation and pathology.

    “The expression and activity of p300 are increased in the brain of AD patients [179], and the dysregulation of p300/CBP promotes tau acetylation, which could aggravate tau accumulation and pathology [46, 48].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [179] Aubry S, Shin W, Crary JF, Lefort R, Qureshi YH, Lefebvre C, Califano A, Shelanski ML. Assembly and interrogation of Alzheimer’s disease genetic networks reveal novel regulators of progression. PLoS ONE. 2015;10: e0120352. source

      Not checked in the free run.

    • cites [46] Min SW, Cho SH, Zhou YG, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010;67:953–66. source

      Not checked in the free run.

    • cites [48] Min SW, Chen X, Tracy TE, Li YQ, Zhou YG, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015;21:1154. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLRP3 inflammasome accumulates inside microglia upon activation, promoting cleavage and activity of caspase-1 and release of IL-1β.

    “NLRP3 inflammasome has been proven to accumulate inside microglia upon activation, promoting cleavage and activity of caspase-1 and release of IL-1β [160].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci. 2018;19:610–21. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Abnormal acetylation of tau on lysine residues spans the microtubule-binding repeat region (MTBR), and this modification alone is sufficient to induce tau pathology and neurodegeneration.

    “Abnormal acetylation of tau on lysine residues spans the microtubule-binding repeat region (MTBR), and this modification alone is sufficient to induce tau pathology and neurodegeneration [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Shin M-K, Vazquez-Rosa E, Koh Y, Dhar M, Chaubey K, Cintron-Perez CJ, Barker S, Miller E, Franke K, Noterman MF, et al. Reducing acetylated tau is neuroprotective in brain injury. Cell. 2021;184:2715–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-10 deletion activates microglia, increases IL-6 production, and leads to tau hyperphosphorylation in response to acute systemic inflammation.

    “Another study demonstrates that IL-10 deletion activates microglia, increases IL-6 production, and leads to tau hyperphosphorylation in response to acute systemic inflammation [165].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Weston LL, Jiang S, Chisholm D, Jantzie LL, Bhaskar K. Interleukin-10 deficiency exacerbates inflammation-induced tau pathology. J Neuroinflammation. 2021;18:161. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau is a substrate of HDAC6, and inhibition of HDAC6 increases tau acetylation.

    “Cohen et al. reported that tau is a substrate of HDAC6, and the inhibition of HDAC6 increases tau acetylation [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, Lee VMY. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun. 2011;2:9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CMKLR1 deletion increases Aβ plaques in the AD mouse brain but reduces mortality and cognitive deficits of AD mice and attenuates tau hyperphosphorylation.

    “Our recent study identified that CMKLR1 deletion increases Aβ plaques in the AD mouse brain but reduces mortality and cognitive deficits of AD mice and attenuates tau hyperphosphorylation [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Zhang HB, Lin AH, Gong P, Chen YQ, Ye RD, Qian F, Zhang Y, Yu Y. The chemokine-like receptor 1 deficiency improves cognitive deficits of AD mice and attenuates tau hyperphosphorylation via regulating tau seeding. J Neurosci. 2020;40:6991–7007. source

      Not checked in the free run.

    • Rests on an assumption: Findings from transgenic mouse models of tau pathology and neuroinflammation are representative of human AD and can guide therapeutic development.

  • May combine two claims.

    Premisecitation

    p47phox expression in neurons contributes to tau hyperphosphorylation directly, while p47phox in astrocytes affects tau hyperphosphorylation by activating astrocytes indirectly.

    “The expression of p47phox in neurons contributes to tau hyperphosphorylation directly, while p47phox in astrocytes affects tau hyperphosphorylation by activating astrocytes indirectly [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Gong P, Chen YQ, Lin AH, Zhang HB, Zhang Y, Ye RD, Yu Y. p47(phox) deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD. Alzheimers Res Ther. 2020;12:18. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau undergoes both N-linked glycosylation and O-linked N-acetylglucosaminylation (O-GlcNAcylation), which have been proposed to affect tau phosphorylation and aggregation.

    “In addition, tau also undergoes both N-linked glycosylation (N-glycosylation) [171] and O-linked N-acetylglucosaminylation (O-GlcNAcylation) [172], which have been proposed to affect tau phosphorylation and aggregation [173].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [171] Losev Y, Frenkel-Pinter M, Abu-Hussien M, Viswanathan GK, Elyashiv-Revivo D, Geries R, Khalaila I, Gazit E, Segal D. Differential effects of putative N-glycosylation sites in human Tau on Alzheimer’s disease-related neurodegeneration. Cell Mol Life Sci. 2021;78:2231–45. source

      Not checked in the free run.

    • cites [172] Zhu YP, Shan XY, Yuzwa SA, Vocadlo DJ. The emerging link between O-GlcNAc and Alzheimer disease. J Biol Chem. 2014;289:34472–81. source

      Not checked in the free run.

    • cites [173] Losev Y, Paul A, Frenkel-Pinter M, Abu-Hussein M, Khalaila I, Gazit E, Segal D. Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity. Sci Rep. 2019;9:10. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibiting p300 with salsalate induces tau deacetylation, preserves tau axonal localization, and protects mice from neurodegeneration.

    “Inhibiting p300 with salsalate, a non-steroidal anti-inflammatory drug, could induce tau deacetylation, preserve tau axonal localization, and protect mice from neurodegeneration [51].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Shin M-K, Vazquez-Rosa E, Koh Y, Dhar M, Chaubey K, Cintron-Perez CJ, Barker S, Miller E, Franke K, Noterman MF, et al. Reducing acetylated tau is neuroprotective in brain injury. Cell. 2021;184:2715–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HDAC6 knockdown attenuates ROS generation, NADPH oxidase activation, and neuroinflammation response in HIV-1 Tat-stimulated astrocytes.

    “HDAC6 knockdown attenuates reactive oxygen species (ROS) generation, NADPH oxidase activation, and neuroinflammation response in HIV-1 transactivator of transcription (Tat)-stimulated astrocytes [184].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Youn GS, Cho H, Kim D, Choi SY, Park J. Crosstalk between HDAC6 and Nox2-based NADPH oxidase mediates HIV-1 Tat-induced pro-inflammatory responses in astrocytes. Redox Biol. 2017;12:978–86. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selective suppression of p38α MAPK significantly reduces tau hyperphosphorylation and improves working memory in hTau mice.

    “Selective suppression of p38α MAPK significantly reduces tau hyperphosphorylation and improves working memory in hTau mice [164].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Maphis N, Jiang SY, Xu GX, Kokiko-Cochran ON, Roy SM, Van Eldik LJ, Watterson DM, Lamb BT, Bhaskar K. Selective suppression of the alpha isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res Ther. 2016;8:54. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 knockout or its R47H variant decreases microgliosis around Aβ plaques and enhances the propagation of tau aggregates.

    “However, another study revealed that TREM2 knockout or its R47H variant decreases microgliosis around Aβ plaques and enhances the propagation of tau aggregates [70].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Leyns CEG, Gratuze M, Narasimhan S, Jain N, Koscal LJ, Jiang H, Manis M, Colonna M, Lee VMY, Ulrich JD, Holtzman DM. TREM2 function impedes tau seeding in neuritic plaques. Nat Neurosci. 2019;22:1217. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With the failures or unsatisfactory efficacy of anti-Aβ drugs, the development of drugs targeting other targets is increasing, such as anti-tau pathology and anti-neuroinflammation.

    “However, with the failures or unsatisfactory efficacy of drugs anti-Aβ [9, 208–211], the development of drugs targeting other targets is increasing, such as anti-tau pathology and anti-neuroinflammation [212].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [9] Mullard A. FDA approval for Biogen’s aducanumab sparks Alzheimer disease firestorm. Nat Rev Drug Discov. 2021;20:496–496.

      Not checked in the free run.

    • cites [208] Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun XY, Thomas RG, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–50. source

      Not checked in the free run.

    • cites [209] Jeremic D, Jimenez-Diaz L, Navarro-Lopez JD. Past, present and future of therapeutic strategies against amyloid-beta peptides in Alzheimer’s disease: a systematic review. Ageing Res Rev. 2021;72:36. source

      Not checked in the free run.

    • cites [210] Salloway S, Chalkias S, Barkhof F, Burkett P, Barakos J, Purcell D, Suhy J, Forrestal F, Tian Y, Umans K, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2022;79:13–21. source

      Not checked in the free run.

    • cites [211] Mahase E. Aducanumab: European agency rejects Alzheimer’s drug over efficacy and safety concerns. BMJ. 2021;375:1.

      Not checked in the free run.

    • cites [212] Cummings J, Lee G, Nahed P, Kambar M, Zhong K, Fonseca J, Taghva K. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement. 2022;8:24.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of TFEB in astrocytes promotes tau fibril species uptake and lysosomal activity as well as attenuates tau spreading and pathology in the hippocampus of P301S tauopathy mice.

    “Overexpression of transcription factor EB (TFEB, a regulator of lysosomal biogenesis) in astrocytes promotes tau fibril species uptake and lysosomal activity as well as attenuates tau spreading and pathology in the hippocampus of P301S tauopathy mice [201] (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Martini-Stoica H, Cole AL, Swartzlander DB, Chen F, Wan YW, Bajaj L, Bader DA, Lee VMY, Trojanowski JQ, Liu ZD, et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J Exp Med. 2018;215:2355–77. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of NLRP3 inhibitor or ASC deficiency reduces exogenously or non-exogenously seeded tau pathology, highlighting the promotion of NLRP3/ASC axis activation on the propagation of tau seeds.

    “Administration of NLRP3 inhibitor or ASC deficiency reduces the exogenously or non-exogenously seeded tau pathology, highlighting the promotion of NLRP3/ASC axis activation on the propagation of tau seeds [186].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] Stancu I-C, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, Lodder C, Brone B, Huaux F, Octave J-N, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019;137:599–617. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau can bind to microglial CX3CR1 and initiate the internalization and degradation of tau.

    “Tau can bind to microglial CX3CR1 and initiate the internalization and degradation of tau [191].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Castro-Sanchez S, Garcia-Yague AJ, Kugler S, Lastres-Becker I. CX3CR1-deficient microglia shows impaired signalling of the transcription factor NRF2: Implications in tauopathies. Redox Biol. 2019;22:12. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau seeds taken up by microglia can activate microglia, further exacerbating tau propagation and pathology.

    “In addition, several studies have shown that tau seeds taken up by microglia can activate microglia, further exacerbating tau propagation and pathology [186, 192, 193].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [186] Stancu I-C, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, Lodder C, Brone B, Huaux F, Octave J-N, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019;137:599–617. source

      Not checked in the free run.

    • cites [192] Jin MH, Shiwaku H, Tanaka H, Obita T, Ohuchi S, Yoshioka Y, Jin XC, Kondo K, Fujita K, Homma H, et al. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nat Commun. 2021;12:22. source

      Not checked in the free run.

    • cites [193] Wang C, Fan L, Khawaja RR, Liu BY, Zhan LH, Kodama L, Chin M, Li YQ, Le D, Zhou YG, et al. Microglial NF-kappa B drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022;13:19. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Suppression of P2RX7-induced exosome secretion from microglia attenuates misfolded tau aggregates in the hippocampus and improves cognitive deficits of P301S mice.

    “Suppression of P2X purinoceptor 7 (P2RX7)-induced exosome secretion from microglia attenuates misfolded tau aggregates in the hippocampus and improves cognitive deficits of P301S mice [195].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] Ruan Z, Delpech JC, Venkatesan Kalavai S, Van Enoo AA, Hu J, Ikezu S, Ikezu T. P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice. Mol Neurodegener. 2020;15:47. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The integrin αV/β1 receptor interacts with tau monomers or fibrils and mediates tau uptake in primary astrocytes.

    “The integrin αV/β1 receptor interacts with tau monomers or fibrils and mediates tau uptake in primary astrocytes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Wang P, Ye YH. Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex. Nat Commun. 2021;12:95. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibitors of O-GlcNAcase enzyme (OGA) like thiamet G increase tau glycosylation, reduce NFTs and neuronal cell death, improve motor behavior, and prolong survival of tau transgenic mice.

    “Inhibitors of the O-GlcNAcase enzyme (OGA)-like thiamet G increase tau glycosylation, reduce NFTs and neuronal cell death, improve motor behavior, and prolong survival of tau transgenic mice [174, 220, 221].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [174] Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012;8:393–9. source

      Not checked in the free run.

    • cites [220] Hastings NB, Wang X, Song L, Butts BD, Grotz D, Hargreaves R, Fred Hess J, Hong KK, Huang CR, Hyde L, et al. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener. 2017;12:39. source

      Not checked in the free run.

    • cites [221] Permanne B, Sand A, Ousson S, Neny M, Hantson J, Schubert R, Wiessner C, Quattropani A, Beher D. O-GlcNAcase inhibitor ASN90 is a multimodal drug candidate for tau and alpha-synuclein proteinopathies. ACS Chem Neurosci. 2022;13:1296–314. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cholinesterase inhibitors and memantine only temporarily relieve symptoms of AD patients but do not delay progression of the disease.

    “These cholinesterase inhibitors and NMDA receptor antagonist memantine only temporarily relieve the symptoms of AD patients but do not delay the progression of the disease [206, 207].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [206] Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics. Mol Med Rep. 2019;20:1479–87.

      Not checked in the free run.

    • cites [207] Kumar A, Singh A. Ekavali: a review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep. 2015;67:195–203. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Various kinases are known to induce tau hyperphosphorylation, such as GSK-3β, a major tau kinase. These kinases are hyperactivated during the progression of AD and other tauopathies.

    “Various kinases are known to induce tau hyperphosphorylation, such as GSK-3β, a major tau kinase. These kinases are hyperactivated during the progression of AD and other tauopathies [19], indicating that the development of their mediators may be an effective treatment for these diseases.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol. 2017;133:665–704. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p38α MAPK is a key kinase involved in microglia-induced neuroinflammation leading to tau pathology, and this kinase can also directly regulate tau phosphorylation.

    “As mentioned above, p38α MAPK is a key kinase involved in microglia-induced neuroinflammation leading to tau pathology [135, 137], and this kinase can also directly regulate tau phosphorylation [39].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [135] 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;138:1738–55. source

      Not checked in the free run.

    • cites [137] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of Tau Pathology by the Microglial Fractalkine Receptor. Neuron. 2010;68:19–31. source

      Not checked in the free run.

    • cites [39] Stefanoska K, Gajwani M, Tan ARP, Ahel HI, Asih PR, Volkerling A, Poljak A, Ittner A. Alzheimer’s disease: ablating single master site abolishes tau hyperphosphorylation. Sci Adv. 2022. https://doi.org/10.1126/sciadv.abl8809. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tideglusib has been reported to reduce tau phosphorylation and has anti-inflammatory effects in animal models.

    “Tideglusib has been reported to reduce tau phosphorylation and has anti-inflammatory effects in animal models [216, 217].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [216] Sereno L, Coma M, Rodriguez M, Sanchez-Ferrer P, Sanchez MB, Gich I, Agullo JM, Perez M, Avila J, Guardia-Laguarta C, et al. A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009;35:359–67. source

      Not checked in the free run.

    • cites [217] Wang H, Huang S, Yan K, Fang X, Abussaud A, Martinez A, Sun HS, Feng ZP. Tideglusib, a chemical inhibitor of GSK3beta, attenuates hypoxic-ischemic brain injury in neonatal mice. Biochim Biophys Acta. 2016;1860:2076–85. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Binding of tau fibrils to astrocyte αV/β1 activates integrin signaling, resulting in NF-κB activation, leading to an increase of pro-inflammatory cytokines and chemokines, and induction of expression of neurotoxic astrocytic markers.

    “The binding of tau fibrils to astrocyte αV/β1 activates integrin signaling, resulting in NF-κB activation, leading to an increase of pro-inflammatory cytokines and chemokines, and induction of expression of neurotoxic astrocytic markers [203].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Wang P, Ye YH. Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex. Nat Commun. 2021;12:95. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with AADvac1 did not slow cognitive and functional decline in mild AD patients in the phase 2 clinical trial (ADAMANT, NCT02579252), although it shows high immunogenicity.

    “However, the treatment of this vaccine did not slow cognitive and functional decline in mild AD patients in the phase 2 clinical trial (ADAMANT, NCT02579252), although it shows the high immunogenicity [227].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [227] Novak P, Kovacech B, Katina S, Schmidt R, Scheltens P, Kontsekova E, Ropele S, Fialova L, Kramberger M, Paulenka-Ivanovova N, et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nature aging. 2021;1:521–34. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Phagocytized tau by astrocytes can be degraded and/or induce astrocytic activation.

    “These findings suggest that phagocytized tau by astrocytes can be degraded and/or induce astrocytic activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Microglia uptake exogenous monomeric tau via LRP1 and TREM2, and then induce NF-κB activation through LRP1/PQBP1/cGAS/STING and TREM2/ERK/PI3K pathways, ultimately triggering neuronal death.

    “Jin et al. reported that microglia uptake exogenous monomeric tau in parallel via two surface receptors, LRP1 and TREM2, and then induce nuclear factor NF-κB activation in microglia through two different pathways, LRP1/polyglutamine binding protein 1 (PQBP1)/cyclic GMP–AMP synthase (cGAS)/Stimulator of interferon genes (STING) and TREM2/extracellular signal-regulated kinase (ERK)/Phosphoinositide”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Jin MH, Shiwaku H, Tanaka H, Obita T, Ohuchi S, Yoshioka Y, Jin XC, Kondo K, Fujita K, Homma H, et al. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nat Commun. 2021;12:22. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Aβ pathology in AD does not always correlate with cognitive decline.

    “The most likely reason for the failure of drugs targeting Aβ may be that Aβ pathology in AD does not always correlate with cognitive decline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The combination of dasatinib and quercetin eliminates senescent cells, reduces tau pathology, amyloid load, and neuroinflammation, and ameliorates cognitive impairment in preclinical studies.

    “This drug combination eliminates the senescent cells (also known as “senolytic therapy”), reduces tau pathology, amyloid load, and neuroinflammation, and ameliorates cognitive impairment in preclinical studies [256, 257].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [256] Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, Mattson MP. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019;22:719–28. source

      Not checked in the free run.

    • cites [257] Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018;17: e12840. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Neuroinflammation may be the third pathological feature of AD and plays an integral role in AD pathogenesis and the promotion of cognitive impairment.

    “Accumulating evidence indicates that neuroinflammation may be the third pathological feature of AD and plays an integral role in AD pathogenesis and the promotion of cognitive impairment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In the middle and late stages of AD, sustained and increased inflammatory responses in glial cells and neurons are pivotal drivers and regulators of the exacerbation of tau pathology, further worsening it by promoting inflammatory responses.

    “While in the middle and late stages of AD, sustained and increased inflammatory responses in glial cells and neurons are pivotal cellular drivers and regulators of the exacerbation of tau pathology, further contributing to its worsening by promoting inflammatory responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The efficacy of the two recently FDA-approved Aβ-targeting DMT drugs is controversial and needs further validation.

    “However, the efficacy of these drugs is controversial and needs further validation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Two DMT drugs targeting Aβ have recently received accelerated FDA approval for AD treatment.

  • May combine two claims.

    Premisecitation

    A phase 2 clinical trial in 37 patients with mild to moderate AD showed that nilotinib was well-tolerated and reduced CSF pTau181 at 6 months compared to the placebo group.

    “A phase 2 clinical trial in 37 patients with mild to moderate AD (NCT02947893) showed that nilotinib was well-tolerated and reduced CSF pTau181 at 6 months compared to the placebo group [251].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [251] Turner RS, Hebron ML, Lawler A, Mundel EE, Yusuf N, Starr JN, Anjum M, Pagan F, Torres-Yaghi Y, Shi WK, et al. Nilotinib effects on safety, tolerability, and biomarkers in Alzheimer’s disease. Ann Neurol. 2020;88:183–94. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The most likely reason for the failure of drugs targeting Aβ may be that Aβ pathology in AD does not always correlate with cognitive decline.

    “The most likely reason for the failure of drugs targeting Aβ may be that Aβ pathology in AD does not always correlate with cognitive decline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A multi-center phase 2 clinical trial showed that although a 24-week treatment with neflamapimod did not ameliorate episodic memory in individuals with mild AD, neflamapimod treatment significantly reduces CSF total tau and tau phosphorylated at threonine 181 (pTau181) compared to the placebo group.

    “A multi-center phase 2 clinical trial showed that although a 24-week treatment with neflamapimod did not ameliorate episodic memory in individuals with mild AD, neflamapimod treatment significantly reduces CSF total tau and tau phosphorylated at threonine 181 (pTau181) compared to the placebo group (NCT03402659).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites NCT03402659

      Not checked in the free run.

77 of 77

  • The paper relies on this without support.

    Findings from transgenic mouse models of tau pathology and neuroinflammation are representative of human AD and can guide therapeutic development.

    “TREM2 deficiency in a hTau (expressing human MAPT but not endogenous mouse Mapt) mouse model exacerbates tau phosphorylation and aggregation at the early disease stage [126].”

  • The paper relies on this without support.

    The failure of NSAID clinical trials to improve cognition in AD patients is due to the disease stages of recruited patients rather than to inflammation not being a valid therapeutic target.

    “The outcomes of clinical trials may be related to the disease stages of recruited AD patients.”

  • The paper relies on this without support.

    Nearly all anti-Aβ drugs have failed to show satisfactory therapeutic efficacy in the past two decades.

    “However, nearly, all anti-Aβ drugs have failed to show satisfactory therapeutic efficacy in the past two decades.”

  • The paper relies on this without support.

    Two DMT drugs targeting Aβ have recently received accelerated FDA approval for AD treatment.

    “It is particularly encouraging that two DMT drugs targeting Aβ have recently received accelerated FDA approval for AD treatment.”

  • The paper relies on this without support.

    To date, there are no tau-focused drugs approved by FDA.

    “To date, there are no tau-focused drugs approved by FDA.”

  • The paper relies on this without support.

    Several agents targeting tau post-translational modification and dissemination have recently entered clinical trials for treating AD and other tauopathies.

    “Still, several agents targeting tau post-translational modification and dissemination have recently entered clinical trials for treating AD and other tauopathies.”

  • The paper relies on this without support.

    These therapeutic strategies have shown good safety and tolerability.

    “These therapeutic strategies have shown good safety and tolerability, and clinical trials of their therapeutic effects are underway.”

  • The paper relies on this without support.

    Clinical trials of the therapeutic effects of these strategies are underway.

    “These therapeutic strategies have shown good safety and tolerability, and clinical trials of their therapeutic effects are underway.”
8 of 8

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.

  • AZP2006 trial is described as both ongoing and completed

    Minor

    The text calls NCT04008355 ongoing, while Table 1 lists the same AZP2006 trial as completed.

1 of 1

Cites

1 retracted

Flagged first, then by citations

1 of the 262 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Tai H-C, Ma H-T, Huang S-C, Wu M-F, Wu C-L, Lai Y-T, Li Z-L, Margolin R, Intorcia AJ, Serrano GE, et al. The tau oligomer antibody APNmAb005 detects early-stage pathological tau enriched at synapses and rescues neuronal loss in long-term treatments. BioRxiv. 2022. https://doi.org/10.1101/2022.06.24.497452v1. · DOI
  2. Jordan. K, Mahdavi. K, Haroon. J, Rindner. E, Zielinski. M, Venkatraman. V, Becerra. S, Goodenowe. D, Ahlem. C, Reading. C, et al: Neuroimaging data from a phase 2, open-label study of ne3107 in patients with cognitive decline due to degenerative dementias. In: Clinical Trials on Alzheimer’s Disease (CTAD) Conference; November 29–December 2; San Francisco, California, USA. 2022

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Related

Authors
Chen, Y., & Yu, Y.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
Yu, Yang
ORCID
Yu, Yang
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2023-07-14
Volume
20
Issue
1
Pages
165-165
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-023-02853-3
PMC
PMC10349496
OpenAlex
W4384296800
Cited by
516
References
262
Citations by year
2026: 185 · 2025: 242 · 2024: 79 · 2023: 10
FWCI
18.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Natural Science Foundation of Shanghai (22ZR1434700)
  • National Natural Science Foundation of China (81870835)
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
Alzheimer's disease, tau pathology, neuroinflammation, glial activation, inflammatory signaling, tau-targeted therapy, tauopathy, amyloid-beta, disease-modifying therapy, precision therapy
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Humans, Inflammation, Amyloid beta-Peptides, tau Proteins, Tauopathies

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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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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