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Cited by 409Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Glial contributions to neurodegeneration in tauopathies

Open access
Leyns, Cheryl E. G., Holtzman, David M.·2017·Molecular Neurodegeneration
DOI 10.1186/s13024-017-0192-xPMC PMC5492997
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Abstract

Tauopathies are a broad set of neurodegenerative dementias characterized by aggregation of the tau protein into filamentous inclusions that can be found in neurons and glial cells. Activated microglia, astrocytes and elevated levels of proinflammatory molecules are also pathological hallmarks that are found in brain regions affected by tau pathology. There has been abundant research in recent years to understand the role of gliosis and neuroinflammation in neurodegenerative diseases, particularly in Alzheimer's disease (AD) which is the most common form of dementia. AD is a tauopathy characterized by both extracellular amyloid-β plaques in addition to intracellular neurofibrillary tangles and neuropil threads containing aggregated tau protein. Accumulating evidence suggests that neuroinflammation offers a possible mechanistic link between these pathologies. Additionally, there appears to be a role for neuroinflammation in aggravating tau pathology and neurodegeneration in tauopathies featuring tau deposits as the predominant pathological signature. In this review, we survey the literature regarding inflammatory mechanisms that may impact neurodegeneration in AD and related tauopathies. We consider a physical role for microglia in the spread of tau pathology as well as the non-cell autonomous effects of secreted proinflammatory cytokines, specifically interleukin 1 beta, interleukin 6, tumor necrosis factor alpha and complement proteins. These molecules appear to have direct effects on tau pathophysiology and overall neuronal health. They also indirectly impact neuronal homeostasis by altering glial function. We conclude by proposing a complex role for gliosis and neuroinflammation in accelerating the progression of AD and other tauopathies.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that reactive gliosis and neuroinflammation contribute to tau pathogenesis and neurodegeneration in Alzheimer’s disease and primary tauopathies, with microglia, astrocytes, cytokines, and complement implicated. It proposes that glial activation may both respond to and accelerate tau pathology, though causal direction and therapeutic implications remain unresolved.

Key findings

  • Tauopathies comprise over twenty-five syndromes; activated microglia, astrocytes, and elevated proinflammatory markers are common hallmarks. AD is a secondary tauopathy with Aβ plaques plus tau tangles, while primary tauopathies include PSP, CBD, FTDP-17, PiD, CTE, and AGD.
  • Genetic and environmental risk factors implicate innate immunity: TREM2 variants confer a 2- to 4-fold increased AD risk; ApoEε4 is associated with a 4–12-fold increased risk based on allele dosage; repetitive mild TBI can lead to CTE, and inflammatory effects have been reported up to 17 years post-injury.
  • Microglia may contribute to tau spreading: they take up tau and re-release exosome-associated tau, and pharmacological microglial depletion reduced AT8 p-tau staining and rescued neuronal excitability deficits in tauopathy mouse models, though that study examined only p-tau species, not fibrillar aggregates, and used small animal numbers.
  • Cytokines IL-1β, TNF-α, IL-6 and complement proteins can alter tau phosphorylation via kinases including p38-MAPK, GSK-3β, and cdk5, and affect neuronal/synaptic health; however, IL-1β is not sufficient to cause neurotoxicity or neurodegeneration in the absence of tau, and whether neuroinflammation causes tau pathology or is a response remains debated.

Methods

  • Narrative review surveying literature on inflammatory mechanisms in AD and related tauopathies, including in vitro and in vivo mechanistic studies alongside neuropathology and neuroimaging reports in AD and non-AD tauopathy patients.
  • No primary data or systematic sample; the paper synthesizes cited studies and proposes models in Figs. 1–2 for AD and primary tauopathies.

Limitations

  • Stated: causal direction is unresolved—whether aberrant neuroinflammation causes tau pathophysiology or glial cells respond first to tau toxicity; more pure tauopathy models and primary tauopathy tissue are needed; limited cytokine transcript data exist for rarer tauopathies; no studies have truly tested TNF-α signaling in pure tauopathy models; one microglial exosome study examined only p-tau, not fibrillar aggregates, and used small numbers of animals.
  • Evident: as a narrative review, it lacks a systematic search or quantitative synthesis, and its conclusions depend on cited literature and proposed models rather than new experimental data.

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

Integrity signals

Registry

Crossref · 10.1186/s13024-017-0192-x

Cites

191 of 191 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 119 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Microglia readily take up both soluble and insoluble forms of tau.

    “Microglia readily take up both soluble and insoluble forms of tau [7, 56, 82, 116].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [7] Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–93. source

      Not checked in the free run.

    • cites [56] Wu JW, Herman M, Liu L, Simoes S, Acker CM, Figueroa H, et al. Small Misfolded tau species are internalized via bulk Endocytosis and Anterogradely and Retrogradely transported in neurons. J Biol Chem. 2013;288:1856–70. source

      Not checked in the free run.

    • cites [82] Bolós M, Llorens-Martín M, Jurado-Arjona J, Hernández F, Rábano A, Avila J. Direct evidence of internalization of tau by microglia in vitro and in vivo. J. Alzheimers Dis. 2016;50:77–87. source

      Not checked in the free run.

    • cites [116] Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep. 2015;5:11161. source

      Not checked in the free run.

  • Premisecitation

    ApoEε4 allele is associated with a 4-12-fold increased risk for AD based on allele dosage.

    “Of the three ApoE alleles, ε2, ε3, and ε4, the ApoEε4 allele is associated with a 4–12-fold increased risk based on allele dosage [85, 86].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7:180–4. source

      Not checked in the free run.

    • cites [86] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3. source

      Not checked in the free run.

  • Interpretationreasoning

    Genetic and environmental risk factors for AD and other tauopathies implicate that glial cells and chronic inflammation may have a more active role in the degenerative process than previously thought.

    “Altogether, genetic and environmental risk factors for AD and other tauopathies implicate that glial cells and chronic inflammation may have a more active role in the degenerative process than previously thought.”
    Quote in the paperSubstantial claim
  • Interpretationcitation

    Aberrant gliosis causes detrimental neuroinflammation that can influence tau pathology and accelerate neurodegeneration.

    “The notion that neuroinflammatory processes contribute to disease was once provocative, yet recent studies have uncovered multiple mechanisms by which aberrant gliosis causes detrimental neuroinflammation that can influence tau pathology and accelerate neurodegeneration.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 2002;35:419–32. source

      Not checked in the free run.

    • cites [5] Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353:777–83. source

      Not checked in the free run.

    • cites [6] Lull ME, Block ML. Microglial activation and chronic neurodegeneration. Neurotherapeutics. 2010;7:354–65. source

      Not checked in the free run.

  • Interpretationreasoning

    Environmental factors that promote neuroinflammation contribute to tau pathogenesis.

    “In addition to genetic predisposition, there is evidence that environmental factors that promote neuroinflammation contribute to tau pathogenesis.”
    Quote in the paperSubstantial claim
  • May combine two claims. 53
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Interpretationcitation

    Expression of IL-1β, TNF-α and IL-6 all feed into a cascade that leads to increases in tau hyperphosphorylation, reduction in synapse markers, and neuronal loss.

    “In contrast, expression of IL-1β, TNF-α and IL-6 all feed into a cascade that leads to increases in tau hyperphosphorylation, reduction in synapse markers, and neuronal loss [110].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J. Microglial cell dysregulation in brain aging and neurodegeneration. Front. Aging Neurosci. [Internet]. 2015 [cited 2017 Mar 6];7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26257642 . source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Genetic studies implicate roles for the innate immune system in neurodegenerative diseases, particularly AD.

    “Genetic studies have further implicated roles for the innate immune system in neurodegenerative diseases, particularly AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ApoEε4 has reduced ability to suppress inflammatory stimuli and higher densities of NFTs have been reported in ApoEε4 carriers.

    “Additionally, ApoEε4 has been found to have reduced ability to suppress inflammatory stimuli and higher densities of NFTs have been reported in ApoEε4 carriers [88].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Ohm TG, Kirca M, Bohl J, Scharnagl H, Gross W, März W. Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation. Neuroscience. 1995;66:583–7. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Tau inclusions have been reported in microglia despite a lack of tau expression, providing evidence that pathological tau may transfer between cells in the brain.

    “Tau inclusions have also been reported in microglia [80–82] despite a lack of tau expression, providing further evidence that pathological tau may also be transferring between cells in the brain.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [80] Odawara T, Iseki E, Kosaka K, Akiyama H, Ikeda K, Yamamoto T. Investigation of tau-2 positive microglia-like cells in the subcortical nuclei of human neurodegenerative disorders. Neurosci Lett. 1995;192:145–8. source

      Not checked in the free run.

    • cites [81] Ghoshal N, García-Sierra F, Fu Y, Beckett LA, Mufson EJ, Kuret J, et al. Tau-66: evidence for a novel tau conformation in Alzheimer’s disease. J Neurochem. 2001;77:1372–85. source

      Not checked in the free run.

    • cites [82] Bolós M, Llorens-Martín M, Jurado-Arjona J, Hernández F, Rábano A, Avila J. Direct evidence of internalization of tau by microglia in vitro and in vivo. J. Alzheimers Dis. 2016;50:77–87. source

      Not checked in the free run.

    • Rests on an assumption: The presence of tau inclusions in microglia indicates cell-to-cell transfer rather than phagocytosis of extracellular tau.

  • May combine two claims.

    Interpretationcitation

    TPSO signaling preceded thioflavin-S-positive tangles and MRI-measureable regional atrophy in PS19 mice, implying TPSO PET may be more adept at detecting neuroinflammation induced by tau aggregation.

    “Importantly, TPSO signaling preceded thioflavin-S-positive tangles and MRI-measureable regional atrophy in the mice implying TPSO PET may be more adept at detecting neuroinflammation induced by tau aggregation [111].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Maeda J, Zhang M-R, Okauchi T, Ji B, Ono M, Hattori S, et al. In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer’s disease and related disorders. J Neurosci. 2011;31:4720–30. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau is expressed at low levels in oligodendrocytes and astrocytes, and tau pathology is prevalent in these cells across tauopathies.

    “Although tau is predominantly produced by neurons in the brain, it is expressed at low levels in oligodendrocytes and astrocytes and tau pathology is prevalent in these cells across tauopathies [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Kahlson MA, Colodner KJ. Glial tau pathology in Tauopathies: functional consequences. J Exp Neurosci. 2015;9:43–50.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Once engulfed, tau is either degraded or re-released in exosomes.

    “Once engulfed, tau is either degraded [116] or re-released in exocytosing microvesicles called exosomes [7, 55].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–93. source

      Not checked in the free run.

    • cites [55] Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2012;287:3842–9. source

      Not checked in the free run.

    • cites [116] Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep. 2015;5:11161. source

      Not checked in the free run.

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

    Premisenone given

    Several tauopathies including PSP, CBD, FTDP-17, and AGD exclusively feature 4R tau deposits.

    “Aggregates composed of both 3R and 4R tau are seen in disease states, though curiously several tauopathies including PSP, CBD, FTDP-17, and AGD exclusively feature 4R tau deposits.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol. 2013;12:609–22. source

      Not checked in the free run.

    • cites [2] Arendt T, Stieler JT, Holzer M. Tau and tauopathies. Brain Res Bull. 2016;126:238–92. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuroinflammation may be a significant contributor to secondary cell death immediately following moderate to severe TBI, and inflammatory effects persist up to 17 years post-injury.

    “Neuroinflammation may be a significant contributor to secondary cell death immediately following moderate to severe TBI and inflammatory effects have been shown to persist up to 17 years post-injury [97, 98].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [97] Giunta B, Obregon D, Velisetty R, Sanberg PR, Borlongan CV, Tan J. The immunology of traumatic brain injury: a prime target for Alzheimer’s disease prevention. J Neuroinflammation. 2012;9:185. source

      Not checked in the free run.

    • cites [98] Lozano D, Gonzales-Portillo GS, Acosta S, de la Pena I, Tajiri N, Kaneko Y, et al. Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat. 2015;11:97–106.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inappropriate phosphorylation of tau at serine and threonine residues flanking the microtubule binding domain can lower its affinity for tubulin and inhibit its ability to promote microtubule assembly.

    “Therefore, inappropriate phosphorylation of tau at these regions can lower its affinity for tubulin and inhibit its ability to promote microtubule assembly [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Witman GB, Cleveland DW, Weingarten MD, Kirschner MW. Tubulin requires tau for growth onto microtubule initiating sites. Proc Natl Acad Sci U S A. 1976;73:4070–4. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adoptive transfer of microglia from CX3CR1−/− htau mice into non-transgenic recipients resulted in increased AT8 p-tau staining and p-38-MAPK signaling, which was blocked by co-injection with an IL-1R agonist.

    “adoptive transfer of microglia from CX3CR1−/− htau mice into non-transgenic recipients resulted in increased AT8 p-tau staining and p-38-MAPK signaling which was blocked by co-injection with an IL-1R agonist [137].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, et al. 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.

  • May combine two claims.

    Premisecitation

    Increased IL-6 levels correlate more closely with NFT burden in AD patients rather than neuritic plaques, as well as with age-related cognitive decline in humans.

    “increased IL-6 levels have been shown to correlate more closely with NFT burden in AD patients rather than neuritic plaques [155] as well as age-related cognitive decline in humans [156].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Luterman JD, Haroutunian V, Yemul S, Ho L, Purohit D, Aisen PS, et al. Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia. Arch Neurol. 2000;57:1153–60. source

      Not checked in the free run.

    • cites [156] Weaver JD, Huang M-H, Albert M, Harris T, Rowe JW, Seeman TE. Interleukin-6 and risk of cognitive decline: Mac Arthur studies of successful aging. Neurology. 2002;59:371–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The observations in CX3CR1-deficient htau mice corresponded with a reduction in synaptosome associated protein 25 and learning and memory deficits.

    “These observations corresponded with a reduction in synaptosome associated protein 25, critical for synaptic vesicle fusion, as well as learning and memory deficits.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, et al. 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.

  • May combine two claims.

    Premisecitation

    In mice expressing P301L human tau under an astrocyte-specific promoter, tau accumulation in astrocytes is followed by neuronal degeneration.

    “Finally, neurofilament staining revealed ballooned neurons and axonal degeneration in areas with abundant tau pathology [126].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Forman MS, Lal D, Zhang B, Dabir DV, Swanson E, Lee VM-Y, et al. Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J Neurosci. 2005;25:3539–50. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 supports proliferation of both astrocytes and microglia and enhances microglial phagocytosis.

    “It has been shown to support proliferation of both astrocytes and microglia [151, 152] and enhance microglial phagocytosis [153, 154].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [151] Streit WJ, Hurley SD, McGraw TS, Semple-Rowland SL. Comparative evaluation of cytokine profiles and reactive gliosis supports a critical role for interleukin-6 in neuron-glia signaling during regeneration. J Neurosci Res. 2000;61:10–20. source

      Not checked in the free run.

    • cites [152] Balasingam V, Tejada-Berges T, Wright E, Bouckova R, Yong VW. Reactive astrogliosis in the neonatal mouse brain and its modulation by cytokines. J Neurosci. 1994;14:846–56. source

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    • cites [153] Shafer LL, McNulty JA, Young MRI. Brain activation of monocyte-lineage cells: involvement of interleukin-6. Neuroimmunomodulation. 2002;10:295–304. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Binding of TNFR1 induces apoptotic signaling, while TNFR2 activation results in nuclear entry of NF-kB and promotes transcription of pro-survival genes.

    “Binding of TNFR1 induces apoptotic signaling while TNFR2 activation results in nuclear entry of NF-kB and promotes transcription of pro-survival genes [140, 142].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [140] Vivek Sharma, Vinay Thakur, Shesh Nath Singh, Rajender Guleria. Tumor Necrosis Factor and Alzheimer’s Disease: A Cause and Consequence Relationship. [cited 2017 Mar 6]. Available from: http://www.ejmanager.com/fulltextpdf.php?mno=10750 .

      Not checked in the free run.

    • cites [142] Faustman D, Davis M. TNF receptor 2 pathway: drug target for autoimmune diseases. Nat Rev Drug Discov. 2010;9:482–93. source

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

    Premisecitation

    In cell culture, Aβ stimulates IL-6 release, which leads to microglial differentiation, thought to further enable them to degrade Aβ.

    “In cell culture, Aβ stimulates IL-6 release which leads to microglial differentiation, thought to further enable them to degrade Aβ [154].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, et al. Interleukin-6, a mental cytokine. Brain Res Rev. 2011;67:157–83. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 has been found in Aβ plaques and is elevated in the CSF and plasma of AD patients.

    “Like TNF-α, IL-6 has been found in Aβ plaques and is elevated in the CSF and plasma of AD patients [105].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Wang W-Y, Tan M-S, Yu J-T, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med. [Internet]. 2015 [cited 2017 Mar 6];3. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486922/ .

      Not checked in the free run.

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

    Premisecitation

    TNF-α has two primary receptors: TNFR1, which is constitutively expressed throughout the brain, and TNFR2, which is inducible and primarily localized to glial and endothelial cells.

    “TNF-α has two primary receptors, TNFR1 which is constitutively expressed throughout the brain and TNFR2 which is inducible and primarily localized to glial and endothelial cells [141].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs. 2009;23:713–25. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CX3CR1-deficient htau mice, p38-MAPK levels were significantly increased, while no changes were detected in GSK-3β or p25.

    “Additionally, p38-MAPK levels were significantly increased in CX3CR1 deficient htau mice, though no changes were detected in GSK-3β or p25.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] 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.

    Interpretationcitation

    Neuroinflammation may accelerate tau pathology by influencing its phosphorylation state, cause neuronal dysfunction, and ultimately lead to neurodegeneration.

    “These results add further credence to the hypothesis that neuroinflammation may accelerate tau pathology by influencing its phosphorylation state, cause neuronal dysfunction, and ultimately lead to neurodegeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Genetic deletion of CX3CR1 in htau mice led to substantially increased microglial activation indicated by CD68 staining as well as elevated levels of p-tau and insoluble tau aggregates.

    “Genetic deletion of CX3CR1 in mice expressing human tau under its endogenous promoter (htau mice) led to substantially increased microglial activation indicated by CD68 staining as well as elevated levels of p-tau and insoluble tau aggregates [136].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] 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.

    Interpretationcitation

    IL-1β signaling mediates tau phosphorylation by multiple kinases and results in synapse loss and neuronal dysfunction.

    “Both in vitro and in vivo studies have demonstrated that IL-1β signaling mediates tau phosphorylation by multiple kinases and results in synapse loss and neuronal dysfunction.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IL-1β's effects on tau phosphorylation in mouse models and cell culture translate to human tauopathies.

  • May combine two claims.

    Premisecitation

    Overexpression of TNF-α in 3xTg mice led to enhancement of the local inflammatory environment, increased intracellular Aβ levels and tau hyperphosphorylation.

    “overexpression of TNF-α in 3xTg mice led to enhancement of the local inflammatory environment, increased intracellular Aβ levels and tau hyperphosphorylation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, et al. Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol. 2008;173:1768–82. source

      Not checked in the free run.

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

    Interpretationreasoning

    TNF-α signaling may be important in early disease states, or loss of TNFR1 and TNFR2 may cause developmental deficits that lead to long-term consequences in protein aggregation.

    “This indicates that TNF-α signaling may be important in early disease states or that there were possibly developmental deficits due to the loss of TNFR1 and 2 that led to long term consequences in protein aggregation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Induction of the NF-kB pathway by TNF-α stimulates the release of COX-2 and activation of JNK, which has been shown to phosphorylate tau.

    “Additionally, induction of the NF-kB pathway by TNF-α stimulates the release of the proinflammatory enzyme cyclooxygenase 2 (COX-2) [140], as well as activation of c-Jun N-terminal kinase (JNK) which has been shown to phosphorylate tau [143].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [140] Vivek Sharma, Vinay Thakur, Shesh Nath Singh, Rajender Guleria. Tumor Necrosis Factor and Alzheimer’s Disease: A Cause and Consequence Relationship. [cited 2017 Mar 6]. Available from: http://www.ejmanager.com/fulltextpdf.php?mno=10750 .

      Not checked in the free run.

    • cites [143] Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, et al. JNK plays a key role in tau hyperphosphorylation in Alzheimer’s disease models. J Alzheimers Dis. 2011;26:315–29. source

      Not checked in the free run.

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

    Premisenone given

    In disease, TNF-α has been shown to lead to neuronal apoptosis by activation of caspases 1 and 3, overstimulation of glutamate receptors and inhibition of early long term potentiation dependent on p38-MAPK activation.

    “In disease, TNF-α has been shown to lead to neuronal apoptosis by activation of caspases 1 and 3, overstimulation of glutamate receptors and inhibition of early long term potentiation dependent on p38-MAPK activation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TNF-α levels are elevated in the CSF of AD patients and correlate with disease progression.

    “TNF-α levels were also found to be elevated in the CSF of AD patients and correlate with disease progression [145, 146].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [145] Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol. 1999;19:223–30. source

      Not checked in the free run.

    • cites [146] Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74:1200–5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In young CX3CR1-deficient htau mice, increased microgliosis and IL-1β levels appeared to precede tau pathology, accelerate p38-MAPK activation and p-tau accumulation, and result in reduced hippocampal weight in aged mice.

    “another group also reported increased microgliosis and IL-1β levels in young CX3CR1 deficient htau mice which appeared to precede tau pathology, accelerate p38-MAPK activation and p-tau accumulation, and result in reduced hippocampal weight in aged mice [137].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, et al. 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.

  • May combine two claims.

    Interpretationreasoning

    IL-1β is a pivotal cytokine capable of driving chronic gliosis, influencing tauopathy progression and impacting tau-induced neurodegeneration.

    “Nevertheless, IL-1β is clearly a pivotal cytokine capable of driving chronic gliosis, influencing tauopathy progression and impacting tau-induced neurodegeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IL-6 is a crucial cytokine for micro- and astrogliosis in the brain, conveying paradoxical proinflammatory and neurotrophic effects.

    “IL-6 is a crucial cytokine for micro- and astrogliosis in the brain conveying paradoxical proinflammatory and neurotrophic effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A1 astrocytes lost their ability to promote neuronal survival, growth, synaptogenesis, and phagocytosis and were highly toxic to neurons.

    “A1 astrocytes lost their ability to promote neuronal survival, growth, synaptogenesis, and phagocytosis and were also highly toxic to neurons, though the exact mechanism of toxicity is still unknown [122, 123].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [122] Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7. source

      Not checked in the free run.

    • cites [123] Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391–410. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hong et al. found that C1q was upregulated prior to plaque formation in multiple mouse models of Aβ pathology and co-localized with synaptic markers.

    “Hong et al. found that C1q was also upregulated prior to plaque formation in multiple mouse models of Aβ pathology and co-localized with synaptic markers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6. source

      Not checked in the free run.

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

    Premisenone given

    Initial immunization studies for Aβ were halted due to severe neuroinflammatory adverse events, some of which resulted in death.

    “Initial immunization studies for Aβ were halted due to severe neuroinflammatory adverse events, some of which resulted in death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both microglia and astrocytes have important, active roles in disease processes.

    “However, these studies do suggest that both microglia and astrocytes have important, active roles in disease processes.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Complement signaling may lead to release of proinflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-18.

    “Additionally, complement signaling may lead to a host of other cellular functions including release of proinflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-18 [161].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Gasque P, Fontaine M, Morgan BP. Complement expression in human brain. Biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. J Immunol Baltim Md. 1995;154:4726–33.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 can activate JAK-STAT pathways, NMDA receptors, and p38-MAPK kinases, which all have been shown to contribute to p-tau formation.

    “IL-6 can also activate JAK-STAT pathways, NMDA receptors, and p38-MAPK kinases which all have been shown to contribute to p-tau formation [154, 159].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [154] Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, et al. Interleukin-6, a mental cytokine. Brain Res Rev. 2011;67:157–83. source

      Not checked in the free run.

    • cites [159] Orellana DI, Quintanilla RA, Gonzalez-Billault C, Maccioni RB. Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons. Neurotox Res. 2005;8:295–304. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Tau pathology then progresses through the spread of toxic tau species, neuronal vulnerability, or by a combination of both mechanisms.

    “Tau pathology then progresses through the spread of toxic tau species, neuronal vulnerability, or by combination of both mechanisms.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    IL-18 may impact hyperphosphorylation of tau via cdk5/p35 and GSK-3β kinases.

    “Another study also found that IL-18 may impact hyperphosphorylation of tau via cdk5/p35 and GSK-3β kinases [168].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Ojala JO, Sutinen EM, Salminen A, Pirttilä T. Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells. J Neuroimmunol. 2008;205:86–93. source

      Not checked in the free run.

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

    Premisenone given

    There are currently no treatments capable of curing or even slowing disease progression in tauopathies.

    “Despite the significant clinical and economic burden tauopathies place on society, there are currently no treatments capable of curing or even slowing disease progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gliosis and neuroinflammation are prevalent in tauopathy patient brains and recapitulated across many animal models.

    “Gliosis and neuroinflammation are prevalent in tauopathy patient brains [4, 5, 106] and recapitulated across many animal models [127, 170–174].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 2002;35:419–32. source

      Not checked in the free run.

    • cites [5] Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353:777–83. source

      Not checked in the free run.

    • cites [106] Fernández-Botrán R, Ahmed Z, Crespo FA, Gatenbee C, Gonzalez J, Dickson DW, et al. Cytokine expression and microglial activation in progressive supranuclear palsy. Parkinsonism Relat Disord. 2011;17:683–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFNγ signaling has been shown to lead to tau phosphorylation and acceleration of neuritic tangle pathology, while TGFβ is a key regulator of various microglial factors including CX3CR1 and numerous interleukins.

    “For instance, IFNγ signaling has been shown to lead to tau phosphorylation and acceleration of neuritic tangle pathology while TGFβ has been shown to be a key regulator of various microglial factors including CX3CR1 and numerous interleukins [110, 169].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J. Microglial cell dysregulation in brain aging and neurodegeneration. Front. Aging Neurosci. [Internet]. 2015 [cited 2017 Mar 6];7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26257642 . source

      Not checked in the free run.

    • cites [169] von Bernhardi R, Cornejo F, Parada GE, Eugenín J. Role of TGFβ signaling in the pathogenesis of Alzheimer’s disease. Front Cell Neurosci. 2015;9:426. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Current data indicates that inflammation is initially stimulated by Aβ in AD and that chronic gliosis influences tau pathogenesis.

    “Current data indicates that inflammation is initially stimulated by Aβ in AD and that chronic gliosis influences tau pathogenesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Yoshiyama et al. provided the most compelling evidence to date that microgliosis can precede tau tangle formation and is capable of driving neurodegeneration.

    “Yoshiyama et al. has provided the most compelling evidence to date that microgliosis can precede tau tangle formation and is capable of driving neurodegeneration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53:337–51. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ApoEε2 enhanced synapse elimination by astrocytes while ApoEε4 prevented it.

    “Additionally, ApoEε2 enhanced synapse elimination by astrocytes while ApoEε4 prevented it [166].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Chung W-S, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016;113:10186–91. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some studies have reported that microglia can mediate tau clearance and this is enhanced with tau monoclonal antibody treatment.

    “Some studies have reported that microglia can mediate tau clearance and this is enhanced with tau monoclonal antibody treatment [116, 181].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116] Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep. 2015;5:11161. source

      Not checked in the free run.

    • cites [181] Funk KE, Mirbaha H, Jiang H, Holtzman DM, Diamond MI. Distinct therapeutic mechanisms of tau antibodies: promoting Microglial clearance versus blocking neuronal uptake. J Biol Chem. 2015;290:21652–62. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oligomeric Aβ induced C1q deposition, while C3 was necessary for oligomeric-Aβ-dependent engulfment of synapses by microglia.

    “Furthermore, oligomeric Aβ induced C1q deposition while C3 was necessary for oligomeric-Aβ-dependent engulfment of synapses by microglia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6. source

      Not checked in the free run.

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

    Premisecitation

    Anti-inflammatory molecules like IL-4 and IL-10 may antagonize the proinflammatory effects of IL-1β and IL-6.

    “Meanwhile, anti-inflammatory molecules like IL-4 and IL-10 may antagonize the proinflammatory effects of IL-1β and IL-6 [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Weisman D, Hakimian E, Ho GJ. Interleukins, inflammation, and mechanisms of Alzheimer’s disease. Vitam Horm. 2006;74:505–30. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Initiation of inflammatory pathways may occur differently depending on the disease.

    “However, initiation of inflammatory pathways may occur differently depending on the disease.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    C1q and Aβ operate to activate the complement cascade and drive synapse elimination by microglia in AD.

    “the authors proposed a model where C1q and Aβ operate to activate the complement cascade and drive synapse elimination by microglia in AD [165].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Binding of Fc receptors is known to activate microglia and stimulate release of proinflammatory molecules which can exacerbate the degenerative process.

    “However, binding of Fc receptors is also known to activate microglia and stimulate release of proinflammatory molecules which can exacerbate the degenerative process [182].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [182] Fuller JP, Stavenhagen JB, Teeling JL. New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer’s Disease. Front Neurosci. [Internet]. 2014 [cited 2017 Mar 6];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139653/ . source

      Not checked in the free run.

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

    Premisecitation

    C1q deposition is dependent on ApoE isoforms, with aged human ApoEε4 knock-in mice accumulating significantly more C1q in the hippocampus than ApoEε2 mice.

    “another recent publication reported C1q deposition was dependent on ApoE isoforms, with aged human ApoEε4 knock-in mice accumulating significantly more C1q in the hippocampus than ApoEε2 mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Chung W-S, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016;113:10186–91. source

      Not checked in the free run.

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

    Interpretationreasoning

    It is possible that tau seeds invoke early microglial activation, which in turn accelerates tau pathology and neurodegeneration.

    “Therefore, it is possible that tau seeds invoke early microglial activation, which in turn accelerate tau pathology and neurodegeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The effectorless tau antibody did not stimulate microglial release of IL-1β, TNF-α or IL-6 in vitro, whereas the full Fc effector containing antibody led to neuronal toxicity.

    “In addition, the effectorless tau antibody did not stimulate microglial release of IL-1β, TNF-α or IL-6 in vitro, which in the case of the full Fc effector containing antibody led to neuronal toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Lee S-H, Le Pichon CE, Adolfsson O, Gafner V, Pihlgren M, Lin H, et al. Antibody-mediated targeting of tau in vivo does not require Effector function and Microglial engagement. Cell Rep. 2016;16:1690–700. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment of PS19 mice with the immunosuppressant FK506 beginning at 2 months of age significantly reduced tau pathology and brain atrophy and dramatically increased life-span.

    “the immunosuppressant FK506 was given to the mice beginning at 2 months of age. Not only did treatment significantly reduce tau pathology and brain atrophy, it dramatically increased the life-span of the mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53:337–51. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Neuroinflammation offers one way by which tau biology may be altered in AD through increasing phosphorylation that may promote protein misfolding, though other mechanisms likely also co-exist.

    “Additionally, neuroinflammation offers one way by which tau biology may be altered in AD through increasing phosphorylation that may promote protein misfolding, though other mechanisms likely also co-exist.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Single chain fragment variables derived from an anti-tau antibody decreased p-tau accumulation in the brain of PS19 tau transgenic mice, indicating that microglial activation via the Fc domain of an antibody is not required for the protective effect.

    “A recent paper also showed that single chain fragment variables (scFvs) derived from an anti-tau antibody decreased p-tau accumulation in the brain of PS19 tau transgenic mice indicating that microglial activation via the Fc domain of an antibody is not required for the protective effect of such a treatment [185].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Ising C, Stanley M, Holtzman DM. Current thinking on the mechanistic basis of Alzheimer’s and implications for drug development. Clin Pharmacol Ther. 2015;98:469–71. source

      Not checked in the free run.

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

    Premisecitation

    Interleukins such as IL-18, IL-34, IL-4, IL-10, IL-13, and others have been reported as either up- or downregulated in patient brain tissue, CSF or blood in AD and related tauopathies.

    “Interleukins such as IL-18, IL-34, IL-4, IL-10 IL-13, and others have been reported as either up or downregulated in patient brain tissue, CSF or blood [92, 103, 167].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] López González I, Garcia-Esparcia P, Llorens F, Ferrer I. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies. Int J Mol Sci. [Internet]. 2016 [cited 2017 Feb 27];17. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783939/ . source

      Not checked in the free run.

    • cites [103] Weisman D, Hakimian E, Ho GJ. Interleukins, inflammation, and mechanisms of Alzheimer’s disease. Vitam Horm. 2006;74:505–30. source

      Not checked in the free run.

    • cites [167] Mizuno T, Doi Y, Mizoguchi H, Jin S, Noda M, Sonobe Y, et al. Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-β neurotoxicity. Am J Pathol. 2011;179:2016–27. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Primary tauopathies share many common features with AD, but early mechanisms of neuroinflammation in disease may differ due to the lack of amyloid pathology in pure tauopathies.

    “Primary tauopathies share many common features with AD, but early mechanisms of neuroinflammation in disease may differ due to the lack of amyloid pathology in pure tauopathies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Certain features are shared between AD and other diseases that feature tau aggregation, but there are also some clear distinctions.

    “Certain features are shared between AD and other diseases that feature tau aggregation, but there are also some clear distinctions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This may then initiate a positive feedback loop that amplifies microglial activation, co-activates astrocytes, and aggravates pathways influencing tau hyperphosphorylation and aggregation.

    “This may then initiate a positive feedback loop, similar to that for AD, which amplifies microglial activation, co-activates astrocytes, and aggravates pathways influencing tau hyperphosphorylation and aggregation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    It may be that tau aggregates are the spark needed for cellular dysfunction in the brain, and neuroinflammation the accelerant for disease progression.

    “It may be that tau aggregates are the spark needed for cellular dysfunction in the brain, and neuroinflammation the accelerant for disease progression.”
    Quote in the paperNot a substantial claim
62 of 62

  • The paper relies on this without support.

    Findings from animal models of tauopathy (e.g., transgenic mice, Drosophila) are relevant to human tauopathies.

    “While these are admittedly artificial models of astrocytic tauopathy, they demonstrate that tau accumulation in astrocytes is sufficient to cause neuronal degeneration.”

  • The paper relies on this without support.

    Markers of glial activation in postmortem tissue and PET imaging reflect active neuroinflammatory processes that contribute to disease progression.

    “TPSO signal has been shown to increase with microglia activation in tauopathies including AD, PSP, PiD, and FTDP-17 [111–113] as well as several other neurodegenerative diseases and injury models such as other frontotemporal dementias (FTDs), Parkinson’s disease, stroke and TBI [114].”

  • The paper relies on this without support.

    Cytokine upregulation in brain tissue is detrimental rather than a compensatory response.

    “Both phenotypes have been reported in disease states making their roles in neurodegeneration unclear [105].”

  • The paper relies on this without support.

    Mechanisms of tau spreading observed in cell culture and mouse models apply to human tauopathies.

    “In vivo tau spreading models further support this potential mechanism of tau propagation in that injection of recombinant tau fibrils or brain lysate containing tau aggregates into the brains of wildtype or young transgenic mice can induce robust pathology at the site of injection and in anatomically connected regions [69–73].”

  • The paper relies on this without support.

    The A1 astrocyte subtype identified in mice is relevant to human AD and other tauopathies.

    “Importantly, this group has demonstrated that A1 astrocytes are upregulated in AD and other neurodegenerative disorders, though additional tauopathies were not tested.”

  • The paper relies on this without support.

    IL-1β's effects on tau phosphorylation in mouse models and cell culture translate to human tauopathies.

    “Both in vitro and in vivo studies have demonstrated that IL-1β signaling mediates tau phosphorylation by multiple kinases and results in synapse loss and neuronal dysfunction.”

  • The paper relies on this without support.

    The presence of tau inclusions in microglia indicates cell-to-cell transfer rather than phagocytosis of extracellular tau.

    “Tau inclusions have also been reported in microglia [80–82] despite a lack of tau expression, providing further evidence that pathological tau may also be transferring between cells in the brain.”

  • The paper relies on this without support.

    Findings from mouse models of tauopathy and in vitro systems are representative of human tauopathies.

    “Gliosis and neuroinflammation are prevalent in tauopathy patient brains [4, 5, 106] and recapitulated across many animal models [127, 170–174].”

  • The paper relies on this without support.

    Inflammatory markers such as CD68 and CD11b staining and cytokine levels indicate microglial activation and neuroinflammation that is causally relevant to tau pathology.

    “Genetic deletion of CX3CR1 in mice expressing human tau under its endogenous promoter (htau mice) led to substantially increased microglial activation indicated by CD68 staining as well as elevated levels of p-tau and insoluble tau aggregates [136].”

  • The paper relies on this without support.

    Reducing p-tau or tau pathology in mouse models will translate to clinical benefit in human tauopathies.

    “A recent study reported that an Fc-effectorless tau antibody reduced p-tau in vivo akin to the full-effector antibody with the same epitope specificity and affinity [184].”
10 of 10

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?

  • Microglia can phagocytose extracellular pathological tau.

    “Given that microglia can phagocytose extracellular pathological tau [148, 149], and that tau misfolds and acquires toxic gain-of-function properties in our vascular amyloid model [120], tau ablation likely reduces this pathological burden.”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [148]

  • The interactive effects of Tau pathology and gliosis on neurodegeneration were studied previously.

    “The interactive effects of Tau pathology and gliosis on neurodegeneration were studied previously64”

    From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [64]

  • 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].”

    From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [114]

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Authors
Leyns, C. E. G., & Holtzman, D. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Holtzman, David M.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2017-06-29
Volume
12
Issue
1
Pages
50-50
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-017-0192-x
PMC
PMC5492997
OpenAlex
W2725377723
Semantic Scholar
6d93bbe0e8df20e00ba3055fed0b53b0cc209f51
Cited by
409
References
191
Citations by year
2026: 32 · 2025: 38 · 2024: 48 · 2023: 51 · 2022: 46 · 2021: 58 · 2020: 45 · 2019: 45 · 2018: 33 · 2017: 11
FWCI
4.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (NS090934)
  • National Institute on Aging (AG04867801, AG053976)
  • Tau Consoritum
  • JPB Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
tauopathy, Alzheimer's disease, neuroinflammation, gliosis, microglia, astrocytes, tau aggregation, neurofibrillary tangles, inflammatory cytokines, IL-1β, interleukin-6, TNF-α, complement proteins, non-cell-autonomous effects, neurodegeneration, disease progression
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Neuroglia, Neurofibrillary Tangles, tau Proteins, Tauopathies

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 2026-10-06.

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

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