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Cited by 1,616Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsAlzheimer's disease research and treatments

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Open access
Gao, Chao, Jiang, Jingwen, Tan, Yuyan, Chen, Shengdi·2023·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-023-01588-0PMC PMC10514343
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Abstract

Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington’s disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes the biology of microglia and their roles across nine neurodegenerative diseases, arguing that reactive microglia are highly heterogeneous and act as a "double-edged sword" that both clears and propagates pathological protein aggregates. It catalogs microglia-targeted therapeutic strategies with preclinical and clinical evidence, concluding that modulating neuroinflammation is the most widely pursued approach.

Key findings

  • Microglia are not a simple M1/M2 binary; single-cell technologies (scRNA-seq, snRNA-seq, CyTOF) have identified disease-specific states such as disease-associated microglia (DAMs) localized near Aβ plaques in AD, and distinct Aβ- and tau-associated signatures in patients.
  • Microglia both protect and harm: they phagocytose Aβ, tau, α-syn, and TDP-43, but excessive uptake impairs phagocytosis and triggers neuroinflammation; microglia also propagate pathology as mobile vehicles and via exosomes (e.g., MGnD microglia hypersecrete pTau-containing EVs).
  • TREM2 is a central node: the R47H variant confers a 2- to 4-fold increased AD risk, and TREM2 p.R47H is a risk factor for FTD (OR = 5.06; p = 0.001); TREM2 effects on tau differ by disease stage.
  • Clinical translation is mixed: minocycline reduced microglial activation on PET in MSA but showed no clinical benefit (NCT00146809) and had harmful effects in ALS (NCT00047723); verdiperstat improved clinical scores and reduced neuroinflammation in a 12-week phase 2 MSA trial (NCT02388295); IONIS-HTTRx produced a 40% reduction in CSF mHTT at the two highest doses.

Methods

Narrative review; no primary data collection or meta-analysis. The authors synthesize mechanistic, preclinical (cell and mouse model), and clinical trial evidence across AD, PD, MSA, ALS, FTD, PSP, CBD, DLB, and HD, and compile a table of interventions with mouse-model findings and trial design, sample size, duration, and outcomes.

Limitations

The paper states that microglial heterogeneity and dynamics during disease progression still need to be better clarified, and that it is beyond its scope to thoroughly review all progress in microglial research. Evident from the text: many mechanistic conclusions rest on mouse models and postmortem tissue, and the authors repeatedly note unresolved questions (e.g., whether early microglial activation in DLB is protective or deleterious, and whether microglial activation in MSA is secondary to α-syn aggregation or neuronal loss). Several cited trials are listed as ongoing, recruiting, or completed without posted results, so their outcomes are not yet evaluable.

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

Integrity signals

Registry

Crossref · 10.1038/s41392-023-01588-0

Cites

556 of 556 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 482 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    Microglia act as a mobile vehicle to propagate protein aggregates.

    “Microglia also act as a mobile vehicle to propagate protein aggregates.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Microglia activation is observed in various neurodegenerative diseases.

    “Microglia activation is observed in various neurodegenerative diseases.”
    • Also stated in: § Introduction · plain
      “Reactive microglia that refer to microglia undergoing morphological, molecular, and functional remodeling in response to brain challenges (i.e., amyloid β [Aβ] or α-synuclein [α-syn] deposition, infected, damaged, or degenerating neurons) have been observed in various neurodegenerative diseases.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Savage, J. C., Carrier, M. & Tremblay, M. E. Morphology of microglia across contexts of health and disease. Methods Mol. Biol. 2034, 13–26 (2019). source

      Not checked in the free run.

    • cites [12] Bouvier, D. S. et al. High resolution dissection of reactive glial nets in Alzheimer’s disease. Sci. Rep. 6, 24544 (2016). source

      Not checked in the free run.

  • Premisecitation

    Microglia exert protective function by phagocytosing and clearing pathological protein aggregates.

    “Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Sarlus, H. & Heneka, M. T. Microglia in Alzheimer’s disease. J. Clin. Invest. 127, 3240–3249 (2017). source

      Not checked in the free run.

  • Interpretationreasoning

    Microglia dysfunction can be an active inducer of the initiation and progression of various neurodegenerative diseases.

    “Importantly, microglia dysfunction can be an active inducer of the initiation and progression of various neurodegenerative diseases.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Microglia are derived from yolk sac (YS) erythromyeloid precursors (EMPs).

    “it is now well-established that microglia are derived from yolk sac (YS) erythromyeloid precursors (EMPs).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). source

      Not checked in the free run.

    • cites [43] Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 23
  • May combine two claims. 186

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

    Premisecitation

    Microglia are the resident macrophages of the central nervous system.

    “Microglia, the resident macrophages of the central nervous system (CNS), utilize their specific receptor repertoire to monitor the microenvironment dynamically in the brain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Arcuri, C., Mecca, C., Bianchi, R., Giambanco, I. & Donato, R. The pathophysiological role of microglia in dynamic surveillance, phagocytosis and structural remodeling of the developing CNS. Front. Mol. Neurosci. 10, 191 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reactive microglia exhibit high spatial and temporal heterogeneity and unique disease-related signatures without correspondence to the canonical M1/M2 classification in neurodegenerative diseases.

    “Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity.”
    • Also stated in: § Introduction · plain
      “Recent advances in scRNA-seq and snRNA-seq technologies have identified high spatial and temporal heterogeneity levels and unique disease-related signatures of these reactive microglia without correspondence to the canonical M1/M2 classification in neurodegenerative diseases.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017). source

      Not checked in the free run.

    • cites [14] Friedman, B. A. et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep. 22, 832–847 (2018). source

      Not checked in the free run.

    • cites [15] Gerrits, E. et al. Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer’s disease. Acta Neuropathol. 141, 681–696 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Extracellular vesicles released from microglia and autophagy impairment in microglia contribute to pathological progression and neurodegeneration.

    “Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression.

    “peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression.”
    • Also stated in: § Conclusion · plain
      “Peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions.

    “Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Savage, J. C., Carrier, M. & Tremblay, M. E. Morphology of microglia across contexts of health and disease. Methods Mol. Biol. 2034, 13–26 (2019). source

      Not checked in the free run.

    • cites [12] Bouvier, D. S. et al. High resolution dissection of reactive glial nets in Alzheimer’s disease. Sci. Rep. 6, 24544 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Microglia play detrimental roles due to excessive uptake of protein aggregates, which leads to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration.

    “play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Microglial activation is more varied and dynamic than anticipated in -omics features and functional consequences, indicating microglia respond differently in different diseases.

    “However, microglia activation is more varied and dynamic than ever anticipated, both in -omics features and functional consequences, indicating that microglia respond differently in different diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    DAMs were localized near Aβ plaques and participated in the clearance of β-amyloid.

    “Notably, DAMs were localized near Aβ plaques and participated in the clearance of β-amyloid.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both intrinsic factors (species, sex, genetic background) and extrinsic factors (pathogens, nutrition, microbiota) influence microglial states.

    “Both intrinsic factors (species, sex, genetic background, etc.) and extrinsic factors (pathogens, nutrition, microbiota, etc.) influence microglial states.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Paolicelli, R. C. et al. Microglia states and nomenclature: a field at its crossroads. Neuron 110, 3458–3483 (2022). source

      Not checked in the free run.

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

    Premisenone given

    Microglial activation is observed in various neurodegenerative diseases.

    “Microglia activation was observed in various neurodegenerative diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microglial cell colonization of the CNS is evolutionarily conserved across vertebrate species and occurs before the formation of neuroectoderm-derived glial cell types such as oligodendrocytes and astrocytes.

    “Microglial cell colonization of the CNS is evolutionarily conserved across vertebrate species and occurs before the formation of the neuroectoderm-derived glial cell types such as oligodendrocytes and astrocytes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Verney, C., Monier, A., Fallet-Bianco, C. & Gressens, P. Early microglial colonization of the human forebrain and possible involvement in periventricular white-matter injury of preterm infants. J. Anat. 217, 436–448 (2010). source

      Not checked in the free run.

    • cites [49] Schlegelmilch, T., Henke, K. & Peri, F. Microglia in the developing brain: from immunity to behaviour. Curr. Opin. Neurobiol. 21, 5–10 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Primary EMPs, secondary EMP-derived fetal liver monocytes, and HSC-derived fetal liver monocytes contribute to all tissue macrophages, with microglia arising solely from primary EMP.

    “Thus, primary EMPs, secondary EMP-derived fetal liver monocytes, and HSC-derived fetal liver monocytes contribute to all tissue macrophages, with microglia arising solely from primary EMP.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Li, Q. & Barres, B. A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Once A1 astrocytes are induced, they lose their essential functions such as supporting neuronal survival, and they also promote neuroinflammation, which contributes to the progression of neurodegenerative diseases.

    “Once A1 astrocytes are induced, they lose their essential functions such as supporting neuronal survival, and they also promote neuroinflammation, which contributes to the progression of neurodegenerative diseases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Yun, S. P. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018). source

      Not checked in the free run.

    • The authors state this as an assumption: The M1/M2 and A1/A2 classifications, although inaccurate, are helpful for elucidating microglia-astrocyte interaction.

  • May combine two claims.

    Premisecitation

    Microglia communicate with nearly all cell types in the brain to facilitate developmental process, maintain homeostasis, assist in tissue repair, and contribute to the pathogenesis of diseases.

    “Microglia communicate with nearly all cell types in the brain to facilitate developmental process, maintain homeostasis, assist in tissue repair, and contribute to the pathogenesis of diseases.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Prinz, M., Masuda, T., Wheeler, M. A. & Quintana, F. J. Microglia and central nervous system-associated macrophages-from origin to disease modulation. Annu. Rev. Immunol. 39, 251–277 (2021). source

      Not checked in the free run.

    • cites [97] Frost, J. L. & Schafer, D. P. Microglia: architects of the developing nervous system. Trends Cell Biol. 26, 587–597 (2016). source

      Not checked in the free run.

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

    Premisecitation

    Microglia phagocytose misfolded proteins, cellular debris, and dying cells to maintain homeostasis.

    “Microglia phagocytose misfolded proteins, cellular debris, and dying cells to maintain homeostasis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Sarlus, H. & Heneka, M. T. Microglia in Alzheimer’s disease. J. Clin. Invest. 127, 3240–3249 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The primary pathological features of AD are extraneuronal amyloid plaques formed by Aβ deposition and intracellular NFTs caused by abnormal tau aggregation.

    “The primary pathological features of AD are extraneuronal amyloid plaques formed by the deposition of Aβ peptide in the brain and intracellular neurofibrillary tangles (NFTs) caused by abnormal aggregation of tau protein.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Duyckaerts, C., Delatour, B. & Potier, M. C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 118, 5–36 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 is expressed highly and exclusively in microglia in the brain.

    “TREM2 is expressed highly and exclusively in microglia in the brain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Jay, T. R., von Saucken, V. E. & Landreth, G. E. TREM2 in neurodegenerative diseases. Mol. Neurodegener. 12, 56 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MGnD microglia hypersecrete EVs containing phosphorylated tau, accelerating tau propagation in a humanized APP mouse model.

    “In a humanized APP mouse model, MGnD microglia, a class of disease-reactive microglia common in neurodegeneration, hypersecrete EVs containing phosphorylated tau (pTau), accelerating tau propagation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Clayton, K. et al. Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model. Mol. Neurodegener. 16, 18 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an AD mouse model, disease-associated microglia (DAM) participate in the clearance of Aβ and are localized near Aβ plaques.

    “Keren-Shaul et al.13 first identified a subgroup of microglia in AD, termed disease-associated microglia (DAM), which participated in the clearance of Aβ. DAMs were localized near Aβ plaques”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 promotes conversion of microglia to the DAM phenotype, which is responsible for Aβ phagocytosis.

    “TREM2 has been reported to promote the conversion of microglia to the DAM phenotype, which is responsible for Aβ phagocytosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LANDO in microglia facilitates Aβ receptor recycling, increasing Aβ surface receptors, thus promoting Aβ clearance.

    “LC3-associated endocytosis (LANDO) in microglia facilitates Aβ receptor recycling, increasing Aβ surface receptors, thus promoting Aβ clearance”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Heckmann, B. L. et al. LC3-associated endocytosis facilitates beta-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell 178, 536–551.e514 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chronic stimulation by growing pathological deposits converts protective microglia to dysfunctional microglia, aggravating AD progression.

    “However, when these growing pathological deposits chronically stimulate microglia, the protective microglia may convert to dysfunctional microglia, aggravating the disease progression of AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aβ binds to microglial TREM2, activating TREM2 signaling and leading to enhanced phagocytosis.

    “Aβ binds to microglial TREM2, which activates TREM2 signaling and lead to the enhanced phagocytosis of microglia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [174] Hammond, T. R., Marsh, S. E. & Stevens, B. Immune signaling in neurodegeneration. Immunity 50, 955–974 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACE-1 inhibition in microglia facilitates transition from homeostatic to DAM-1 signature and enhances amyloid clearance and improves cognitive performance in AD mice.

    “BACE-1 inhibition in microglia facilitated the microglia phenotype transition from homeostatic to stage 1 disease-associated microglia (DAM-1) signature148 and thus enhanced amyloid clearance and improved cognitive performance in AD mice.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [148] Singh, N. et al. BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1. Sci. Adv. 8, eabo1286 (2022). source

      Not checked in the free run.

    • cites [149] Singh, N., Das, B., Zhou, J., Hu, X. & Yan, R. Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance. Sci. Adv. 8, eabo3610 (2022). source

      Not checked in the free run.

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    Premisecitation

    NgR-deficient AD mice have reduced amyloid burden and improved cognitive impairment.

    “In contrast, NgR-deficient AD mice reduced amyloid burden and improved cognitive impairment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Wang, J. et al. Nogo receptor impairs the clearance of fibril amyloid-beta by microglia and accelerates Alzheimer’s-like disease progression. Aging Cell 20, e13515 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ASC specks released from microglia bind to and promote cross-seeding of Aβ, leading to amyloid seeding and spreading of amyloid pathology.

    “After being released from microglia, ASC specks bind to and promote the cross-seeding of Aβ, leading to amyloid seeding and spreading of amyloid pathology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature 552, 355–361 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of TREM2 function impairs Aβ phagocytosis by microglia and increases amyloid seeding in AD mouse models.

    “Loss of TREM2 function impaired Aβ phagocytosis by microglia and increased amyloid seeding in AD mouse models.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [169] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015). source

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    • cites [170] Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22, 191–204 (2019). source

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    Premisecitation

    Compared with APOE4, APOE3 lipoproteins induce faster microglial migration towards Aβ, facilitate Aβ uptake, and ameliorate cognition.

    “Compared with APOE4, APOE3 lipoproteins induce faster microglial migration towards Aβ, facilitate Aβ uptake, and ameliorate cognition.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Fitz, N. F. et al. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease. Nat. Commun. 12, 3416 (2021). source

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    Premisecitation

    Enhancing TREM2 signaling by TREM2 agonist antibody, direct delivery of TREM2 gene, or stimulating other pathways increases TREM2 expression in AD mice, enhances Aβ phagocytosis, and improves cognitive behaviors.

    “enhancing TREM2 signaling by TREM2 agonist antibody, direct delivery of the TREM2 gene, or stimulating other pathways to increase TREM2 expression in the brains of AD mice enhanced Aβ phagocytosis and improved cognitive behaviors.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [171] Schlepckow, K. et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol. Med. 12, e11227 (2020). source

      Not checked in the free run.

    • cites [172] Wang, S. et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J. Exp. Med. 217, e20200785 (2020). source

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    • cites [173] Zhao, P. et al. A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease. Sci. Transl. Med. 14, eabq0095 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AD1-microglia are localized near Aβ plaques and strongly correlated with tissue Aβ load.

    “AD1-microglia were localized near Aβ plaques and were strongly correlated with the tissue Aβ load.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microglial autophagy deficiency leads to dysregulation of lipid metabolism, induces a pro-inflammatory state, and enhances intraneuronal tau pathology and its spreading.

    “Microglial autophagy deficiency can lead to dysregulation of lipid metabolism, induce microglia into a pro-inflammatory state, and as a result, enhance intraneuronal tau pathology and its spreading.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Xu, Y., Propson, N. E., Du, S., Xiong, W. & Zheng, H. Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading. Proc. Natl Acad. Sci. USA 118, e2023418118 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With aging, NgR expression on microglia increases, impairing microglial phagocytosis and clearance of Aβ.

    “With aging, the Nogo receptor (NgR) expression on microglia increased, impairing microglial phagocytosis and clearance of Aβ.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Wang, J. et al. Nogo receptor impairs the clearance of fibril amyloid-beta by microglia and accelerates Alzheimer’s-like disease progression. Aging Cell 20, e13515 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the early stage of AD, the microglial response may be protective; reactive microglia migrate to pathological deposits and engulf and eliminate them.

    “In the early stage of the disease, this response may be protective. The reactive microglia migrate to the vicinity of pathological deposits such as Aβ or tau and then engulf and eliminate them.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LANDO-deficient AD mice induced neurodegeneration and memory deficits.

    “in contrast, LANDO-deficient AD mice induced neurodegeneration and memory deficits.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Heckmann, B. L. et al. LC3-associated endocytosis facilitates beta-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell 178, 536–551.e514 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Midbrain microglia have decreased complexity compared to striatal microglia and show a muted reaction to inflammatory stimulus, displaying a tolerogenic rather than primed phenotype.

    “the microglia in the midbrain had a decreased complexity compared to those in the striatum, showing that midbrain microglia had a muted reaction to an inflammatory stimulus, displaying a tolerogenic rather than primed phenotype.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Uriarte Huarte, O. et al. Single-cell transcriptomics and in situ morphological analyses reveal microglia heterogeneity across the nigrostriatal pathway. Front. Immunol. 12, 639613 (2021). source

      Not checked in the free run.

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    Premisecitation

    In postmortem midbrain samples, PD patients have an increased number of reactive microglia and a reduction in oligodendrocyte numbers compared to controls.

    “the researchers observed an increased number in reactive microglia and a reduction in oligodendrocyte numbers in PD patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [215] Smajic, S. et al. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145, 964–978 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The microglial activation trajectory extends from P2RY12high cells to two activation branches, one with highly expressed HSP90AA1 or IL1B and the other containing GPNMBhigh cells.

    “The microglial activation trajectory extends from P2RY12high cells to two activation branches, one with highly expressed HSP90AA1 or IL1B241 cells and the other containing GPNMBhigh cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [215] Smajic, S. et al. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145, 964–978 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Peripheral inflammation can affect the brain through the blood-brain barrier or the autonomic nervous system, triggering microglial activation and contributing to neurodegeneration.

    “Peripheral inflammation can also affect the brain through the blood-brain barrier or the autonomic nervous system, triggering microglial activation and contributing to neurodegeneration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [225] Ferrari, C. C. & Tarelli, R. Parkinson’s disease and systemic inflammation. Parkinsons Dis. 2011, 436813 (2011).

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In early stages of AD, TREM2 may suppress tau seeding, but later in AD, it may aggravate tau propagation.

    “Responding to tau pathology, in the early stages of AD, TREM2 may suppress tau seeding, but later in AD, it may aggravate tau propagation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Fibrinogen leaked from cerebrovascular damage binds to CD11b on microglia; this interaction mediates microglial activation, leading to spine loss and cognitive deficits in 5×FAD mice.

    “Fibrinogen leaked from the site of cerebrovascular damage into the brain and subsequently bound to the receptor CD11b on the surface of microglia. The interaction of fibrinogen and CD11b mediated microglial activation led to spine loss and promoted cognitive deficits in the 5×FAD mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Merlini, M. et al. Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer’s disease model. Neuron 101, 1099–1108.e1096 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A higher level of NLRP3 inflammasome has been observed in microglial cells in the SN of PD patients, linked to secretion of pro-inflammatory cytokines associated with neurodegeneration.

    “A higher level of NLRP3 inflammasome has been observed in microglial cells in the SN of PD patients, which has been linked to the secretion of pro-inflammatory cytokines associated with neurodegeneration.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [223] Gordon, R. et al. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med. 10, eaah4066 (2018). source

      Not checked in the free run.

    • cites [224] Haque, M. E. et al. Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease. Mov. Disord. 35, 20–33 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 deficiency significantly reduces brain atrophy and prevents microglial activation in tau transgenic mice.

    “other studies found that TREM2 deficiency significantly reduced brain atrophy and prevented microglial activation in tau transgenic mice.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [178] Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017). source

      Not checked in the free run.

    • cites [179] Sayed, F. A. et al. Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc. Natl Acad. Sci. USA 115, 10172–10177 (2018). source

      Not checked in the free run.

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

    Premisenone given

    PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of misfolded α-syn in Lewy bodies.

    “Pathologically, PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) as well as the accumulation of misfolded α-syn in Lewy bodies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Microglia are a double-edged sword in AD: they phagocytose Aβ and tau, limit propagation of Aβ and tau pathology, and can also accelerate Aβ and tau spreading and lead to neurodegeneration.

    “Overall, microglia are a double-edged sword in AD. Microglia phagocytose Aβ and tau, limit propagation of Aβ and tau pathology, and can also accelerate Aβ and tau spreading and lead to neurodegeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Microglia and sTREM2 play a protective role in AD.

    “which supports the hypothesis that microglia and sTREM2 play a protective role in AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chronically depleting microglia before and during plaque development in two AD transgenic mouse models significantly reduces PNN loss, indicating that microglia promote plaque-dependent PNN loss.

    “Chronically depleting microglia before and during plaque development in two AD transgenic mouse models significantly reduced PNN loss, indicating that microglia promote plaque-dependent PNN loss.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Crapser, J. D. et al. Microglia facilitate loss of perineuronal nets in the Alzheimer’s disease brain. EBioMedicine 58, 102919 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The p.H157Y mutation located at the cleavage site of TREM2 extracellular domain significantly increases TREM2 shedding with elevated sTREM2 levels in brain and serum but is associated with increased AD risk.

    “the mutation p.H157Y located at the cleavage site of TREM2 extracellular domain significantly increased TREM2 shedding with elevated sTREM2 levels in the brain and serum but associated with increased AD risk.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [192] Schlepckow, K. et al. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol. Med. 9, 1356–1365 (2017). source

      Not checked in the free run.

    • cites [193] Thornton, P. et al. TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Mol. Med. 9, 1366–1378 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP/PS1 mice treated with Trem2 knockdown ASOs at late stages exhibit a 50% reduction in plaque load, while administration at early stages does not affect plaque load.

    “APP/PS1 mice treated with Trem2 knockdown antisense oligonucleotides (ASOs) through the ventricles at late stages exhibited a 50% reduction in plaque load. In contrast, administration of ASOs at early stages did not affect plaque load.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [180] Schoch, K. M. et al. Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice. Proc. Natl Acad. Sci. USA 118, e2100356118 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial activation is discovered not only in individuals with long-term illnesses but also in patients who were just diagnosed with PD.

    “Notably, microglial activation was discovered not only in individuals with long-term illnesses but also in patients who were just diagnosed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Gerhard, A. et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol. Dis. 21, 404–412 (2006). source

      Not checked in the free run.

    • Rests on an assumption: Increases in TSPO-PET ligand binding in AD and PD brains reflect microglial activation.

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

    Premisecitation

    Reactive microglia were first observed in the substantia nigra of postmortem brain tissue from PD patients in 1988.

    “In 1988, reactive microglia were first observed in the substantia nigra (SN) of postmortem brain tissue from PD patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [210] McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38, 1285–1291 (1988). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial activation begins early and persists throughout the course of PD.

    “Microglial activation begins early and persists throughout the course of PD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [209] Janda, E., Boi, L. & Carta, A. R. Microglial phagocytosis and its regulation: a therapeutic target in Parkinson’s disease? Front. Mol. Neurosci. 11, 144 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the 5×FAD mouse model and human cortical tissue, extensive loss of PNNs is observed, and the loss of PNNs is proportional to plaque burden.

    “In the 5×FAD mouse model and human cortical tissue, extensive loss of PNNs has been observed, and the loss of PNNs was proportional to plaque burden.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Crapser, J. D. et al. Microglia facilitate loss of perineuronal nets in the Alzheimer’s disease brain. EBioMedicine 58, 102919 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Dysfunctional microglia in AD promote the clearance of synapses and PNNs and impair neuronal plasticity and activity.

    “The above studies indicated that dysfunctional microglia in AD promoted the clearance of synapses and PNNs and impaired neuronal plasticity and activity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    sTREM2 directly binds to neurons in mouse models of AD and inhibits LTP induction.

    “experimental evidence revealed that sTREM2 directly bound to neurons in mouse models of AD194 and inhibited LTP induction.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [194] Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018). source

      Not checked in the free run.

    • cites [195] Moutinho, M. et al. TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation. Genome Med. 15, 11 (2023). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a murine model, a distinct subset of microglia in the midbrain displays an intrinsic transcriptional immune alerted signature, with some genes exclusively overexpressed and absent in other brain regions such as the striatum.

    “Using scRNA-seq and immunofluorescence analyses in a murine model, the researchers identified a distinct subset of microglia in the midbrain that displayed an intrinsic transcriptional immune alerted signature. Notably, some genes, including Casp4, Ccl4, Cd83, and H2-ab1, were exclusively overexpressed in the immune alerted subset. Interestingly, this subset was absent in other brain regions, such”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Uriarte Huarte, O. et al. Single-cell transcriptomics and in situ morphological analyses reveal microglia heterogeneity across the nigrostriatal pathway. Front. Immunol. 12, 639613 (2021). source

      Not checked in the free run.

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

    Premisenone given

    Extracellular α-syn exposure increases pro-inflammatory cytokine production in microglial cells.

    “Extracellular α-syn exposure increases pro-inflammatory cytokine production in microglial cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The CX3CL1-CX3CR1 signaling pathway is essential for maintaining a healthy balance in microglial activity, regulating chemoattraction and synaptic plasticity, and reducing microglia-mediated inflammation and neurotoxicity.

    “Studies have suggested that the CX3CL1-CX3CR1 signaling pathway is essential for maintaining a healthy balance in microglial activity, regulating chemoattraction and synaptic plasticity, and reducing microglia-mediated inflammation and neurotoxicity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [252] Pabon, M. M., Bachstetter, A. D., Hudson, C. E., Gemma, C. & Bickford, P. C. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J. Neuroinflammation 8, 9 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Compared to healthy controls, PD patients have increased frequencies of Th1 cells and higher levels of IL10 and IL17A in their serum.

    “Compared to healthy controls, PD patients had increased frequencies of Th1 cells and higher levels of IL10 and IL17A in their serum.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CD200 is expressed on the surface of neurons and interacts with microglial CD200R; dysregulation of the CD200-CD200R pathway is linked to increased microglial activation and degeneration of dopaminergic neurons.

    “Another protein that regulates microglial activation is CD200, which is expressed on the surface of neurons and interacts with microglial CD200R. Dysregulation of the CD200-CD200R pathway has been linked to increased microglial activation and degeneration of dopaminergic neurons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [253] Zhang, S. et al. CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson’s disease. J. Neuroinflammation 8, 154 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LPS/IFN-γ induces microglial activation and increases exosome release; microglia-derived exosomes facilitate transmission of α-syn to neurons, accelerating neuronal death.

    “Additionally, LPS/IFN-γ induces microglial activation, increases exosome release,235 and microglia-derived exosomes facilitate the transmission of α-syn to neurons, accelerating neuronal death.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [235] Tsutsumi, R. et al. Involvement of exosomes in dopaminergic neurodegeneration by microglial activation in midbrain slice cultures. Biochem. Biophys. Res. Commun. 511, 427–433 (2019). source

      Not checked in the free run.

    • cites [236] George, S. et al. Microglia affect alpha-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease. Mol. Neurodegener. 14, 34 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Production of neuroinflammation may trigger α-syn oligomerization, leading to a harmful cycle of microglial activation.

    “Production of neuroinflammation may trigger α-syn oligomerization, leading to a harmful cycle of microglial activation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Allen Reish, H. E. & Standaert, D. G. Role of alpha-synuclein in inducing innate and adaptive immunity in Parkinson disease. J. Parkinsons Dis. 5, 1–19 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LRRK2 expression is particularly high in various immune cells, including microglia, macrophages, and monocytes, and relatively low in T cells.

    “Previous studies have shown that LRRK2 expression is particularly high in various immune cells, including microglia, macrophages, and monocytes. In contrast, its expression in T cells is relatively low.258,259”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [258] Thevenet, J., Pescini Gobert, R., Hooft van Huijsduijnen, R., Wiessner, C. & Sagot, Y. J. Regulation of LRRK2 expression points to a functional role in human monocyte maturation. PLoS ONE 6, e21519 (2011). source

      Not checked in the free run.

    • cites [259] Moehle, M. S. et al. LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci. 32, 1602–1611 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial CB2 receptor activation is neuroprotective and improves motor symptoms in several animal models of PD.

    “Several animal models of PD show that microglial CB2 receptor activation is neuroprotective and improves motor symptoms.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [254] Price, D. A. et al. WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Eur. J. Neurosci. 29, 2177–2186 (2009). source

      Not checked in the free run.

    • cites [255] Chung, Y. C. et al. CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Exp. Mol. Med. 48, e205 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upregulation and activation of CCR2 have been observed in PD mouse models and patients, suggesting a detrimental role of infiltrating monocytes in PD.

    “Studies in PD mouse models and patients have shown upregulation and activation of CCR2, suggesting a detrimental role of infiltrating monocytes in PD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [230] Hall, S. et al. Cerebrospinal fluid concentrations of inflammatory markers in Parkinson’s disease and atypical parkinsonian disorders. Sci. Rep. 8, 13276 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extracellular α-syn is taken up by microglia, perhaps via the autophagy receptor p62, and degraded by selective autophagy.

    “Extracellular α-syn is taken up by microglia, perhaps via the autophagy receptor p62, and degraded by selective autophagy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Choi, I. et al. Microglia clear neuron-released alpha-synuclein via selective autophagy and prevent neurodegeneration. Nat. Commun. 11, 1386 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The phagocytic ability of microglia is crucial for α-syn clearance and thus plays a role in the development of PD.

    “The phagocytic ability of microglia is crucial for α-syn clearance and thus plays a role in the development of PD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Zhang, W. et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 19, 533–542 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia-specific chromatin regions regulate LRRK2 expression, and a specific regulatory DNA element containing the PD-associated genetic variant rs6581593 modulates LRRK2 expression in microglia.

    “The researchers identified microglia-specific chromatin regions that regulated LRRK2 expression and showed that a specific regulatory DNA element containing the PD-associated genetic variant rs6581593 modulates LRRK2 expression in microglia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [261] Langston, R. G. et al. Association of a common genetic variant with Parkinson’s disease is mediated by microglia. Sci. Transl. Med. 14, eabp8869 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia take up and degrade α-syn, and internalization can activate microglia and cause neuroinflammation.

    “As CNS monitors, microglia take up and degrade α-syn, whose internalization can activate microglia and cause neuroinflammation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [238] Grozdanov, V. & Danzer, K. M. Release and uptake of pathologic alpha-synuclein. Cell Tissue Res. 373, 175–182 (2018). source

      Not checked in the free run.

    • cites [239] Choi, I. et al. Microglia clear neuron-released alpha-synuclein via selective autophagy and prevent neurodegeneration. Nat. Commun. 11, 1386 (2020). source

      Not checked in the free run.

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

    Premisecitation

    DJ-1 dysfunction is implicated in a small percentage (1-2%) of inherited forms of early-onset PD.

    “DJ-1 dysfunction is implicated in a small percentage (1–2%) of inherited forms of early-onset PD.256”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] Blauwendraat, C., Nalls, M. A. & Singleton, A. B. The genetic architecture of Parkinson’s disease. Lancet Neurol. 19, 170–178 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    α-syn overexpression drives microglia polarization towards a pro-inflammatory phenotype, resulting in increased production of inflammatory cytokines such as IL-1β, IL-6, and TNF-α, as well as enzymes such as COX-2 and iNOS, and the generation of free radicals.

    “α-syn overexpression has been shown to drive microglia polarization towards a pro-inflammatory phenotype, resulting in increased production of inflammatory cytokines such as IL-1β, IL-6, and TNF-α, as well as enzymes such as COX-2 and iNOS, and the generation of free radicals.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [242] Ardah, M. T., Merghani, M. M. & Haque, M. E. Thymoquinone prevents neurodegeneration against MPTP in vivo and modulates alpha-synuclein aggregation in vitro. Neurochem. Int. 128, 115–126 (2019). source

      Not checked in the free run.

    • cites [243] Sarkar, S. et al. Molecular signatures of neuroinflammation induced by αSynuclein aggregates in microglial cells. Front. Immunol. 11, 33 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of LRRK2 kinase activity leads to phosphorylation of NF-κB inhibitory subunit p50 at PKA-specific site S337, resulting in abnormally higher nuclear P-p50, which may inhibit NF-κB function and prevent efficient DNA binding and gene transcription activation in response to inflammation.

    “Furthermore, inhibition of LRRK2 kinase activity can lead to the phosphorylation of NF-κB inhibitory subunit p50 at the protein kinase A (PKA) -specific phosphorylation site S337. This results in an abnormally higher proportion of nuclear P-p50, which may inhibit the function of NF-κB, preventing efficient DNA binding and gene transcription activation in response to inflammation.262”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [262] Russo, I. et al. Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-kappaB p50 signaling in cultured microglia cells. J. Neuroinflammation 12, 230 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR2 and TLR4 play a role in the uptake of α-syn and subsequent activation of microglia, boosting α-syn clearance by microglia.

    “TLRs, including TLR2 and TLR4, are receptors expressed on microglia, which were demonstrated to play a role in the uptake of α-syn and the subsequent activation of microglia, boosting α-syn clearance by microglia.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [246] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). source

      Not checked in the free run.

    • cites [247] Kim, C. et al. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4, 1562 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Different conformation states of α-syn can activate microglia in PD, leading to increased secretion of IL-6, IL-1β, and NO.

    “Different conformation states of α-syn can activate microglia in PD, leading to increased secretion of IL-6, IL-1β, and NO.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Calabresi, P. et al. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 14, 176 (2023). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    α-syn-triggered phagocytic activity of microglia is critical for α-syn clearance and prevents accumulation of misfolded α-syn.

    “α-syn-triggered phagocytic activity of microglia is critical for α-syn clearance and prevents accumulation of misfolded α-syn.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Astrocytes convert MPTP into MPP+; MPP+ inhibits mitochondrial complex 1, resulting in ATP depletion and oxidative stress, leading to death of dopaminergic cells and activation of pro-inflammatory microglia.

    “Astrocytes convert MPTP into MPP+. Dopamine receptors in neurons take up MPP+, which inhibits the mitochondrial complex 1 of the electron transport chain, resulting in ATP depletion and oxidative stress. Ultimately, this leads to the death of dopaminergic cells and the activation of pro-inflammatory microglia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Tieu, K. A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 1, a009316 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The CX3CR1 receptor expressed on microglia specifically recognizes CX3CL1 and is critical in neuron-microglia communication.

    “Several studies have revealed that the CX3CR1 receptor expressed on microglia is critical in neuron-microglia communication. This receptor specifically recognizes the protein CX3CL1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [251] Harrison, J. K. et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl Acad. Sci. USA 95, 10896–10901 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    α-syn-induced microglial activation depends on TLRs 1/2 signaling and TLR4 signaling.

    “The α-syn-induced microglial activation depends on TLRs 1/2 signaling294 and TLR4 signaling.246”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [294] Daniele, S. G. et al. Activation of MyD88-dependent TLR1/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal 8, ra45 (2015). source

      Not checked in the free run.

    • cites [246] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Via a specific interaction with TLRs, misfolded α-syn directly activates microglia and promotes production and release of pro-inflammatory cytokines.

    “The above evidence indicates that via a specific interaction with TLRs, the misfolded α-syn directly activates microglia and promotes the production and release of pro-inflammatory cytokines.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [294] Daniele, S. G. et al. Activation of MyD88-dependent TLR1/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal 8, ra45 (2015). source

      Not checked in the free run.

    • cites [246] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia lacking DJ-1 show increased mitochondrial activity, leading to elevated ROS compared with normal microglia, and this effect is further increased by LPS treatment.

    “In addition, microglia lacking DJ-1 showed increased mitochondrial activity, leading to elevated levels of ROS compared to normal microglia, and this effect was further increased by treatment with LPS.265”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [265] Trudler, D., Weinreb, O., Mandel, S. A., Youdim, M. B. & Frenkel, D. DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline. J. Neurochem. 129, 434–447 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia can phagocytize α-syn, but excessive uptake of α-syn by microglia leads to neurodegeneration.

    “Evidence consistently showed that microglia could phagocytize α-syn, but excessive uptake of α-syn by microglia led to neurodegeneration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [295] Stefanova, N. et al. Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 179, 954–963 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR4-mediated α-syn phagocytosis by microglia induces NF-κB translocation, ROS production, and release of pro-inflammatory cytokines such as TNF-α.

    “TLR4-mediated α-syn phagocytosis by microglia245,246,295 and induced NF-κB translocation, ROS production, and the release of pro-inflammatory cytokines such as TNF-α.246,296”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [245] Venezia, S. et al. Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal alpha-synucleinopathy. Mol. Neurodegener. 12, 52 (2017). source

      Not checked in the free run.

    • cites [246] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). source

      Not checked in the free run.

    • cites [295] Stefanova, N. et al. Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 179, 954–963 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In DJ-1 KO mice, microglia exhibit increased phosphorylation levels of STAT1 and increased inflammatory mediators COX-2, iNOS, and TNF-α.

    “In DJ-1 KO mice, microglia exhibited increased expression of phosphorylation levels of STAT1, as well as inflammatory mediators COX-2, iNOS, and TNF-α.264”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [264] Kim, J. H. et al. DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: a novel anti-inflammatory function of DJ-1. Neurobiol. Dis. 60, 1–10 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR stimulation with a TLR4 selective agonist (monophosphoryl lipid A) in the same MSA mouse model ameliorated motor deficits and rescued nigral neurodegeneration.

    “In contrast, TLR stimulation with a TLR4 selective agonist (monophosphoryl lipid A) in the same MSA mouse model ameliorated motor deficits and rescued nigral neurodegeneration.245”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [245] Venezia, S. et al. Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal alpha-synucleinopathy. Mol. Neurodegener. 12, 52 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    α-syn aggregated in microglia led to a significant decrease in microglial phagocytic ability and triggered an inflammatory response, increasing release of pro-inflammatory factors, ROS, and nitric oxide, creating a toxic environment that eventually led to neurodegeneration.

    “Mechanistic studies have found that α-syn aggregated in microglia led to a significant decrease in the phagocytic ability of microglia and triggered an inflammatory response, increasing the release of pro-inflammatory factors, ROS, and nitric oxide by microglia, which created a toxic environment eventually led to neurodegeneration295”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [295] Stefanova, N. et al. Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 179, 954–963 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Various factors including abnormal α-syn accumulation, microglial activation and neuroinflammation, autophagic impairment, mitochondrial dysfunction, and proteasomal dysfunction are involved in the pathogenesis of MSA.

    “Mechanismly, various factors including the abnormal accumulation of α-syn, microglial activation and neuroinflammation,276 autophagic impairment,277–279 mitochondrial,280 and proteasomal dysfunction281,282 are involved in the pathogenesis of MSA.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [276] Stefanova, N. et al. Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy. Mov. Disord. 22, 2196–2203 (2007). source

      Not checked in the free run.

    • cites [277] Monzio Compagnoni, G. et al. Mitochondrial dysregulation and impaired autophagy in iPSC-derived dopaminergic neurons of multiple system atrophy. Stem Cell Rep. 11, 1185–1198 (2018). source

      Not checked in the free run.

    • cites [278] Schwarz, L., Goldbaum, O., Bergmann, M., Probst-Cousin, S. & Richter-Landsberg, C. Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes. J. Mol. Neurosci. 47, 256–266 (2012). source

      Not checked in the free run.

    • cites [279] Tanji, K. et al. Alteration of autophagosomal proteins in the brain of multiple system atrophy. Neurobiol. Dis. 49, 190–198 (2013). source

      Not checked in the free run.

    • cites [280] Nakamoto, F. K. et al. The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy. Sci. Rep. 8, 14215 (2018). source

      Not checked in the free run.

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

    Premisecitation

    Mutations in the SOD1 gene occur in approximately 20% of ALS cases.

    “Mutations in the SOD1 gene (encoding superoxide dismutase 1) occur in ~20% of cases,305”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [305] Rosen, D. R. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364, 362 (1993). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Upregulated TLRs may have a protective effect by increasing microglial phagocytosis of α-syn, but as a result induce neuroinflammation and promote neurodegeneration.

    “Upregulated TLRs are a double-edged sword. It may have a protective effect by increasing the phagocytosis of α-syn by microglia, but as a result, it induces neuroinflammation and promotes neurodegeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the same MSA mouse model, the proportion of Th1 T cells and the level of INF-γ cytokine in striatal tissue were significantly increased.

    “Meanwhile, in the same MSA mouse model, the proportion of Th1 T cells and the level of INF-γ cytokine in the striatal tissue were significantly increased.301”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [301] Williams, G. P. et al. T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease. Acta Neuropathol. 139, 855–874 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Postmortem and in vivo PET studies revealed widespread cerebral microglial activation in patients with ALS and even in pre-symptomatic ALS-related mutation carriers.

    “Postmortem studies308–310 and in vivo PET studies311–313 revealed widespread cerebral microglial activation in patients with ALS,308–312 and even in pre-symptomatic ALS-related mutation carriers.309,313”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [308] Henkel, J. S. et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann. Neurol. 55, 221–235 (2004). source

      Not checked in the free run.

    • cites [309] Brettschneider, J. et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS ONE 7, e39216 (2012). source

      Not checked in the free run.

    • cites [310] Nolan, M. et al. Quantitative patterns of motor cortex proteinopathy across ALS genotypes. Acta Neuropathol. Commun. 8, 98 (2020). source

      Not checked in the free run.

    • cites [311] Turner, M. R. et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol. Dis. 15, 601–609 (2004). source

      Not checked in the free run.

    • cites [312] Zurcher, N. R. et al. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28. Neuroimage Clin. 7, 409–414 (2015). source

      Not checked in the free run.

    • cites [313] Tondo, G. et al. (11) C-PK11195 PET-based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis. Ann. Clin. Transl. Neurol. 7, 1513–1523 (2020). source

      Not checked in the free run.

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

    Premisecitation

    Mutation in C9orf72 accounts for 40% of familial ALS and FTD cases.

    “Mutation in C9orf72 accounts for 40% of familial ALS and FTD cases.303,304”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [303] Renton, A. E., Chio, A. & Traynor, B. J. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17, 17–23 (2014). source

      Not checked in the free run.

    • cites [304] DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ninety-seven percent of patients with ALS and 50% of patients with FTD have cytoplasmic TDP-43 aggregates within neurons.

    “Ninety-seven percent of patients with ALS and 50% of patients with FTD have cytoplasmic TDP-43 aggregates within neurons,332”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [332] Irwin, D. J. et al. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol. 129, 469–491 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial activation was observed in SOD1 models and was detected before the onset of clinical disease in some studies.

    “Microglial activation was observed in SOD1 models, and microglial activation was detected before the onset of clinical disease in some studies.330,331”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [330] Alexianu, M. E., Kozovska, M. & Appel, S. H. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57, 1282–1289 (2001). source

      Not checked in the free run.

    • cites [331] Hall, E. D., Oostveen, J. A. & Gurney, M. E. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23, 249–256 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunohistochemical staining of postmortem brains found that NLRP3 inflammasome was significantly upregulated compared with controls and significantly correlated with deposition of GCIs and neurodegeneration in the putamen of MSA.

    “Immunohistochemical staining of postmortem brains found that the NLRP3 inflammasome was significantly upregulated compared with controls and was significantly correlated with the deposition of GCIs and neurodegeneration in the putamen of MSA299”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [299] Li, F., Ayaki, T., Maki, T., Sawamoto, N. & Takahashi, R. NLRP3 inflammasome-related proteins are upregulated in the putamen of patients with multiple system atrophy. J. Neuropathol. Exp. Neurol. 77, 1055–1065 (2018). source

      Not checked in the free run.

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

    Premisecitation

    Mutations in TARDBP and FUS have a lower frequency (<5%) in ALS.

    “while mutations in TARDBP (encoding TAR DNA- binding protein 43 [TDP43])306 and FUS (encoding the fused in sarcoma protein) have a lower frequency (<5%).307”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [306] Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008). source

      Not checked in the free run.

    • cites [307] Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human SOD1 mutant mice exhibit progressive paralysis, pathological protein aggregation, motor neuron degeneration, and gliosis, which are hallmarks of ALS patients.

    “The human SOD1 mutant mice (mSOD1) are widely used as ALS models because they exhibit progressive paralysis, pathological protein aggregation, motor neuron degeneration, and gliosis, which are hallmarks of ALS patients.325–327”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [325] Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994). source

      Not checked in the free run.

    • cites [326] Philips, T. & Rothstein, J. D. Rodent models of amyotrophic lateral sclerosis. Curr. Protoc. Pharmacol. 69, 5.67.1–5.67.21 (2015). source

      Not checked in the free run.

    • cites [327] Turner, B. J. & Talbot, K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog. Neurobiol. 85, 94–134 (2008). source

      Not checked in the free run.

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

    Premisecitation

    Pathological studies have shown deposition of abnormal proteins in FTD brain tissues, including TDP-43 (50% of cases), tau (40% of cases), and FUS (5-10% of cases).

    “Pathological studies have shown the deposition of abnormal proteins in the brain tissues of FTD patients, including TDP-43 (50% of cases), tau (40% of cases), and FUS (5–10% of cases).314,315”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [314] Neumann, M. & Mackenzie, I. R. A. Review: Neuropathology of non-tau frontotemporal lobar degeneration. Neuropathol. Appl. Neurobiol. 45, 19–40 (2019). source

      Not checked in the free run.

    • cites [315] Spillantini, M. G. & Goedert, M. Tau pathology and neurodegeneration. Lancet Neurol. 12, 609–622 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Microglia act as a mobile vehicle to propagate α-syn in MSA after uptake instead of degrading misfolded proteins in place.

    “so it was speculated that these microglia acted as a mobile vehicle to propagate α-syn in MSA after uptaking of α-syn instead of degrading these misfolded proteins in place.300”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [300] Valdinocci, D., Grant, G. D., Dickson, T. C. & Pountney, D. L. Epothilone D inhibits microglia-mediated spread of alpha-synuclein aggregates. Mol. Cell Neurosci. 89, 80–94 (2018). source

      Not checked in the free run.

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

    Premisecitation

    It is estimated that 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN, or MAPT genes.

    “It is estimated that 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN, or MAPT genes.316”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [316] Panza, F. et al. Development of disease-modifying drugs for frontotemporal dementia spectrum disorders. Nat. Rev. Neurol. 16, 213–228 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Microglia increase synaptic pruning through interaction with complement, which exacerbates neuronal loss and behavioral abnormalities.

    “In addition, microglia increase synaptic pruning through interaction with complement, which exacerbates neuronal loss and behavioral abnormalities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Heterozygous GRN mutations cause deficiency in progranulin (PGRN), a lysosomal and secreted protein, and contribute to the development of FTD.

    “Heterozygous GRN mutations cause the deficiency in progranulin (PGRN), a lysosomal and secreted protein, and contribute to the development of FTD,337”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [337] Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Grn deficiency leads to microglial lysosomal dysfunction and reduced ability to degrade myelin debris, causing accumulation of myelin debris in microglial lysosomes and increased microgliosis and myelin debris accumulation in white matter of Grn−/− mice and patients with GRN-associated FTD.

    “Grn deficiency led to microglial lysosomal dysfunction and a reduced ability to degrade myelin debris, thus leading to the accumulation of myelin debris in microglial lysosomes and increased microgliosis and myelin debris accumulation in the white matter of Grn−/− mice and patients with GRN-associated FTD.349”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [349] Wu, Y. et al. Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD. Cell Rep. 36, 109581 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TDP-43 interacts with microglial TREM2 and induces TREM2-dependent microglia with phagocytic ability that facilitates clearance of TDP-43.

    “Recently, Xie et al. found that TDP-43 interacted with microglial TREM2 and induced TREM2-dependent microglia with phagocytic ability that facilitated clearance of TDP-43.347”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [347] Xie, M. et al. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat. Neurosci. 25, 26–38 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Grn loss of function causes microglial activation, cytosolic phosphorylated TDP-43 aggregation, myelin debris accumulation in white matter, and spatial learning and memory impairment in Grn-/- mice.

    “Grn loss of function causes microglial activation,339,340 cytosolic phosphorylated TDP-43 aggregation,339,340 myelin debris accumulation in white matter, and spatial learning and memory impairment in Grn -/- mice.340”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [339] Yin, F. et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J. Exp. Med. 207, 117–128 (2010). source

      Not checked in the free run.

    • cites [340] Yin, F. et al. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J. 24, 4639–4647 (2010).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Grn deficiency causes synaptic loss by microglia-mediated synaptic pruning via complement; deletion of C1qa significantly reduced synaptic pruning by Grn-/- microglia and ameliorated behavioral deficits, neuronal cell loss, and increased survival in Grn-/- mice.

    “Deficiency of Grn caused synaptic loss by microglia-mediated synaptic pruning via complement involvement as deletion of the C1qa gene (which encodes complement C1q subcomponent subunit A) significantly reduced synaptic pruning by Grn-/-microglia, and ameliorated behavioral deficits, neuronal cell loss and increased survival in Grn-/- mice.348”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [348] Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Grn loss of function profoundly impacts microglial state and function, which plays a critical role in FTD pathogenesis.

    “In the CNS, Grn loss of function profoundly impacts the microglial state and function, which plays a critical role in FTD pathogenesis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [348] Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016). source

      Not checked in the free run.

    • cites [349] Wu, Y. et al. Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD. Cell Rep. 36, 109581 (2021). source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models of neurodegenerative diseases can be extrapolated to human disease mechanisms.

  • May combine two claims.

    Premisecitation

    In mice lacking TREM2, microglia are locked in a homeostatic state, TDP-43 clearance by microglia is reduced, leading to increased neuronal damage and motor impairments.

    “In mice lacking TREM2, microglia were locked in a homeostatic state, and TDP-43 clearance by microglia was reduced, leading to increased neuronal damage and motor impairments.347”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [347] Xie, M. et al. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat. Neurosci. 25, 26–38 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Microglia could phagocytize pathological protein deposits such as TDP-43, and interaction of TDP-43 with microglial TREM2 promotes phagocytosis and clearance of TDP-43 by microglia.

    “Overall, microglia could phagocytize pathological protein deposits such as TDP-43, and the interaction of TDP-43 with microglial TREM2 promotes the phagocytosis and clearance of TDP-43 by microglia.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [341] Svahn, A. J. et al. Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons. Acta Neuropathol. 136, 445–459 (2018). source

      Not checked in the free run.

    • cites [342] Spiller, K. J. et al. Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat. Neurosci. 21, 329–340 (2018). source

      Not checked in the free run.

    • cites [347] Xie, M. et al. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat. Neurosci. 25, 26–38 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In the disease state, microglial lysosomes undergo dysfunction, reducing clearance of deposited protein and myelin debris and accumulating myelin debris in white matter.

    “In the disease state, microglial lysosomes undergo dysfunction, which reduces the clearance of deposited protein and myelin debris and accumulates myelin debris in the white matter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Mutations in TARDBP identified in patients with ALS or FTD indicate a mechanistic link between TDP-43 and ALS/FTD and suggest a common underlying mechanism.

    “and mutations in TARDBP, the gene encoding TDP-43, have been identified in patients with ALS or FTD,306,333 indicating a mechanistic link between TDP-43 and ALS/FTD and also suggesting a common underlying mechanism”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [306] Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008). source

      Not checked in the free run.

    • cites [333] Benajiba, L. et al. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann. Neurol. 65, 470–473 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced mutant levels in microglia did not have much effect on early disease progression, but substantially slowed it later on.

    “Reduced mutant levels in microglia did not have much effect on early disease progression, but substantially slowed it later on,306”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [306] Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL18RAP 3′UTR variants are protective factors that reduce the risk of developing ALS fivefold, delay onset, and delay the age of death in individuals with ALS.

    “Recently, interleukin-18 receptor accessory protein (IL18RAP) 3′ untranslated region (3′UTR) variants were identified as protective factors which reduced the risk of developing ALS fivefold, delayed onset, and therefore the age of death in individuals with ALS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [358] Eitan, C. et al. Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3’UTR protect against ALS. Nat. Neurosci. 25, 433–445 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGRN is expressed in microglia and neurons and shows higher expression once microglia respond to changes in their CNS environment.

    “PGRN is expressed in microglia and neurons and shows higher expression once microglia respond to the changes in their CNS environment.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [339] Yin, F. et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J. Exp. Med. 207, 117–128 (2010). source

      Not checked in the free run.

    • cites [340] Yin, F. et al. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J. 24, 4639–4647 (2010).

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the context of the TDP-43 mouse model, microglia can phagocytize pathological TDP-43 to play a protective role and drive neuroinflammation, resulting in neuronal damage.

    “Therefore, in the context of the TDP-43 mouse model, microglia can phagocytize pathological TDP-43 to play a protective role and drive neuroinflammation, resulting in neuronal damage.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models of neurodegenerative diseases can be extrapolated to human disease mechanisms.

  • May combine two claims.

    Premisecitation

    Grn deficiency leads to NF-κB activation in microglia and elevation of TNFα, leading to hyperexcitability of medium spiny neurons and obsessive-compulsive disorder-like behavior.

    “Grn deficiency leads to NF-κB activation in microglia and elevation of TNFα, leading to hyperexcitability of medium spiny neurons and obsessive-compulsive disorder-like behavior.357”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [357] Krabbe, G. et al. Microglial NFkappaB-TNFalpha hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. Proc. Natl Acad. Sci. USA 114, 5029–5034 (2017). source

      Not checked in the free run.

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

    Premisecitation

    Homozygous GRN mutation leads to neuronal ceroid lipofuscinosis.

    “while the homozygous GRN mutation leads to neuronal ceroid lipofuscinosis.338”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [338] Smith, K. R. et al. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am. J. Hum. Genet. 90, 1102–1107 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia presented an anti-inflammatory phenotype in SOD1G93A mice at disease onset and were neuroprotective to motor neurons; in contrast, microglia presented a pro-inflammatory phenotype at end-stage disease and were neurotoxic to motor neurons.

    “Another study also found that microglia presented an anti-inflammatory phenotype in SOD1G93A mice at disease onset and were neuroprotective to motor neurons. In contrast, microglia presented a pro-inflammatory phenotype at end-stage disease and were neurotoxic to motor neurons.356”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [356] Liao, B., Zhao, W., Beers, D. R., Henkel, J. S. & Appel, S. H. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp. Neurol. 237, 147–152 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, WT or various forms of mutant TDP43 protein or TDP43 aggregates added to primary microglial cultures were internalized, leading to microglial activation, NLRP3 inflammasome and pro-inflammatory marker upregulation, with mutant TDP43 eliciting a more pronounced response.

    “In vitro studies found when WT or various forms of mutant TDP43 protein or TDP43 aggregates were added to primary microglial cultures, they were internalized, leading to microglial activation, NLRP3 inflammasome and pro-inflammatory markers upregulation, in which mutant TDP43 eliciting a more pronounced response.353”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [353] Leal-Lasarte, M. M., Franco, J. M., Labrador-Garrido, A., Pozo, D. & Roodveldt, C. Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia. FASEB J. 31, 2797–2816 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Loss of function of C9ORF72 may lead to microglial dysfunction, which may accelerate disease progression in C9ALS/FTD patients.

    “the loss of function of C9ORF72 may lead to microglial dysfunction, which may accelerate disease progression in C9ALS/FTD patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [363] Koppers, M. et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 78, 426–438 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Neuropathologically, PSP is defined by accumulation of pTau in both neurons and glial cells.

    “Neuropathologically, PSP is defined by the accumulation of pTau in both neurons and glial cells.369”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [369] Boxer, A. L. et al. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 16, 552–563 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subcortical tau pathology and microglial activation positively correlated with clinical severity and could predict disease progression in PSP.

    “Additionally, subcortical tau pathology and microglial activation positively correlated with clinical severity376,378,379 and could predict disease progression in PSP.379”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [376] Passamonti, L. et al. [(11)C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy. Neurology 90, e1989–e1996 (2018). source

      Not checked in the free run.

    • cites [378] Malpetti, M. et al. Neuroinflammation and tau colocalize in vivo in progressive supranuclear palsy. Ann. Neurol. 88, 1194–1204 (2020). source

      Not checked in the free run.

    • cites [379] Malpetti, M. et al. Neuroinflammation predicts disease progression in progressive supranuclear palsy. J. Neurol. Neurosurg. Psychiatry 92, 769–775 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreased C9orf72 expression in C9-ALS led to altered microglial function and increased microglial activation.

    “Transcriptome and histologic analyses of postmortem tissue from patients with ALS carrying the C9orf72 expansion (C9-ALS) found that decreased C9orf72 expression in C9-ALS led to altered microglial function and increased microglial activation.309,361”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [309] Brettschneider, J. et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS ONE 7, e39216 (2012). source

      Not checked in the free run.

    • cites [361] O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of C9orf72 in microglial cells promoted microglial phagocytosis and neuronal synaptic loss.

    “Co-cultured C9orf72+/+ or C9orf72-/- microglia with WT cortical neurons found that loss of C9orf72 in microglial cells promoted microglial phagocytosis and neuronal synaptic loss.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [362] Lall, D. et al. C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron 109, 2275–2291.e2278 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After antibiotic treatment, homeostatic genes were downregulated and neurodegenerative genes increased in microglia, and the microglia signature change preceded changes in motor function.

    “There was a downregulation of homeostatic genes and an increase in neurodegenerative genes in microglia after antibiotic treatment, and the microglia signature change preceded changes in motor function.359”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [359] Cox, L. M. et al. The microbiota restrains neurodegenerative microglia in a model of amyotrophic lateral sclerosis. Microbiome 10, 47 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Peripheral immune cells shape microglia into a pro-inflammatory phenotype and accelerate disease progression in ALS.

    “The above evidence suggests that peripheral immune cells shape microglia into a pro-inflammatory phenotype and accelerate disease progression in ALS365”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [365] Garofalo, S. et al. Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis. Nat. Commun. 11, 1773 (2020). source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models of neurodegenerative diseases can be extrapolated to human disease mechanisms.

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

    Premisecitation

    Over 30 drugs targeting tau aggregation, processing, and accumulation reached the clinic over the past 15 years, but the results were disappointing.

    “There have been over 30 drugs that target tau aggregation, processing, and accumulation reaching the clinic over the past 15 years, but the results were disappointing.370”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [370] Imbimbo, B. P., Ippati, S., Watling, M. & Balducci, C. A critical appraisal of tau-targeting therapies for primary and secondary tauopathies. Alzheimers Dement. 18, 1008–1037 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL18RAP 3′UTR variants reduce mRNA stability and binding of double-stranded RNA-binding proteins.

    “These variants in the IL18RAP 3′UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [358] Eitan, C. et al. Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3’UTR protect against ALS. Nat. Neurosci. 25, 433–445 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL18RAP is upstream of NF-κB, and the variants downregulate IL18RAP-NF-κB signaling in microglia.

    “Mechanistically, IL18RAP is upstream of NF-κB; thus, the variants downregulate IL18RAP–NF-κB signaling in microglia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [358] Eitan, C. et al. Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3’UTR protect against ALS. Nat. Neurosci. 25, 433–445 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Grn loss of function promoted microglial transition from a homeostatic to a disease-specific state, aggravated TDP-43 pathology and neurodegeneration through synergy of microglia and the complement system; deleting C1qa and C3 mitigated microglial toxicity and rescued TDP-43 proteinopathy and neurodegeneration.

    “Grn loss of function promoted the microglial transition from a homeostatic to a disease-specific state, aggravated TDP-43 pathology and neurodegeneration through the synergy of microglia and the complement system since deleting the genes for C1qa and C3 mitigated microglial toxicity and rescued TDP-43 proteinopathy and neurodegeneration.360”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [360] Zhang, J. et al. Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature 588, 459–465 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Replacing peripheral nerve macrophages at disease onset suppressed peripheral macrophage inflammation, reduced microglial pro-inflammatory responses, and prolonged survival in mice.

    “Replacing peripheral nerve macrophages at disease onset suppressed peripheral macrophage inflammation, reduced microglial pro-inflammatory responses, and prolonged survival in mice.364”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [364] Chiot, A. et al. Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival. Nat. Neurosci. 23, 1339–1351 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NK cell depletion induced a protective microglial phenotype and increased survival in ALS mouse models (hSOD1G93A and TDP43A315T).

    “NK cell depletion induced a protective microglial phenotype and increased survival in the ALS mouse models (hSOD1G93A and TDP43A315T).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [365] Garofalo, S. et al. Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis. Nat. Commun. 11, 1773 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationcitation

    Tauopathy is the primary cause of microglial activation.

    “It has been hypothesized that tauopathy is the primary cause of microglial activation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In C9orf72-/- mice, progressive splenomegaly, lymphadenopathy, and upregulation of pro-inflammatory cytokines were observed at the periphery, while brain and spinal cord microglia showed an inflammatory state.

    “In the C9orf72–/– mice, progressive splenomegaly, lymphadenopathy, and upregulation of pro-inflammatory cytokines were observed at the periphery, while brain and spinal cord microglia showed an inflammatory state.361”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [361] O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial activation colocalized and correlated with tau pathology in PSP patients and transgenic mice expressing mutant tau P301L.

    “Firstly, microglial activation colocalized and correlated with tau pathology in PSP patients374,378 and transgenic mice expressing mutant tau P301L.380”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [374] Ishizawa, K. & Dickson, D. W. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J. Neuropathol. Exp. Neurol. 60, 647–657 (2001). source

      Not checked in the free run.

    • cites [378] Malpetti, M. et al. Neuroinflammation and tau colocalize in vivo in progressive supranuclear palsy. Ann. Neurol. 88, 1194–1204 (2020). source

      Not checked in the free run.

    • cites [380] Sasaki, A. et al. Microglial activation in brain lesions with tau deposits: comparison of human tauopathies and tau transgenic mice TgTauP301L. Brain Res. 1214, 159–168 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antibiotic administration to SOD1 mice altered gut microbiota composition, weakened motor function, and caused death.

    “Antibiotic administration to SOD1 mice altered gut microbiota composition, weakened motor function, and caused death in the SOD1 mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [359] Cox, L. M. et al. The microbiota restrains neurodegenerative microglia in a model of amyotrophic lateral sclerosis. Microbiome 10, 47 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Microglial activation is closely related to tau pathology and neurodegeneration, suggesting that microglia likely play a crucial role in the pathogenesis of PSP.

    “Taken together, the above pathological and neuroimaging evidence consistently showed that microglial activation was closely related to tau pathology and neurodegeneration, suggesting that microglia is likely to play a crucial role in the pathogenesis of PSP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Pathologically, pTau leads to depolymerization of microtubules, neuronal damage, microgliosis, and astrogliosis, ultimately leading to irreversible neurodegeneration.

    “Pathologically pTau leads to depolymerization of microtubules, neuronal damage, microgliosis, and astrogliosis, ultimately leading to irreversible neurodegeneration.370”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [370] Imbimbo, B. P., Ippati, S., Watling, M. & Balducci, C. A critical appraisal of tau-targeting therapies for primary and secondary tauopathies. Alzheimers Dement. 18, 1008–1037 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Despite clearing tau aggregation, microglia also lead to loss of synapses and stressed-but-viable neurons, which disrupt neuronal networks and may lead to cognitive impairment.

    “Despite clearing tau aggregation, microglia also lead to the loss of synapses and stressed-but-viable neurons, which disrupt neuronal networks and may lead to cognitive”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Reactive gliosis is routinely found in the striatum of HD patients, together with reactive fibrillary astrocytosis and reactive microglia.

    “Reactive gliosis is routinely found in the striatum of HD patients, together with reactive fibrillary astrocytosis and reactive microglia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [441] Vonsattel, J. P., Keller, C. & Del Pilar Amaya, M. Neuropathology of Huntington’s disease. Handb. Clin. Neurol. 89, 599–618 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Thy1-hTau.P301S mice, from 2 months onward there was significant cortical pTau deposition, and microglial changes followed pTau accumulation, including morphological changes, increased microglial lysosomal volume, and loss of homeostatic marker Tmem119.

    “From 2 months onward, there was significant cortical pTau deposition, and several changes were observed in microglia following pTau accumulation, including morphological changes, an increase in microglial lysosomal volume, and a significant loss of homeostatic marker Tmem119.381”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [381] van Olst, L. et al. Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model. Neurobiol. Aging 89, 89–98 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Microglia could phagocytize free extracellular tau, synapses of neurons containing pTau, and even live neurons containing tau inclusion.

    “Together, microglia could phagocytize free extracellular tau, synapses of neurons containing pTau, and even live neurons containing Tau inclusion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Microglial activation leads to the release of pro-inflammatory factors and induces neuroinflammation, further accelerating the accumulation of hyperphosphorylated tau.

    “Microglial activation led to the release of pro-inflammatory factors and induced neuroinflammation, further accelerating the accumulation of hyperphosphorylated tau.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [393] Lee, D. C. et al. LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J. Neuroinflammation 7, 56 (2010). source

      Not checked in the free run.

    • cites [394] Gorlovoy, P., Larionov, S., Pham, T. T. & Neumann, H. Accumulation of tau induced in neurites by microglial proinflammatory mediators. FASEB J. 23, 2502–2513 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aggregated tau activates the ASC inflammasome via the NLRP3-ASC axis, which exacerbates exogenously seeded and non-exogenously seeded tau pathology in vivo.

    “These findings indicate that aggregated tau activates the ASC inflammasome via the NLRP3-ASC axis, which exacerbates exogenously seeded and non-exogenously seeded tau pathology in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [399] Stancu, I. C. et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 137, 599–617 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Microglia and their secreted exosomes contribute to tauopathy progression, and inhibition of exosome synthesis or secretion could be a therapeutic target.

    “Overall, microglia and their secreted exosomes contribute to tauopathy progression and the inhibition of exosome synthesis or secretion could be a therapeutic target.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Studies of human postmortem brain tissue consistently showed increased cortical recruitment of T lymphocytes in DLB, suggesting that adaptive immunity may be involved in the pathogenesis of DLB.

    “Although these studies of human postmortem brain tissue did not demonstrate microglial activation in DLB patients, they consistently showed increased cortical recruitment of T lymphocytes in DLB,420,424 suggesting that adaptive immunity may be involved in the pathogenesis of DLB.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [420] Amin, J. et al. Neuroinflammation in dementia with Lewy bodies: a human post-mortem study. Transl. Psychiatry 10, 267 (2020). source

      Not checked in the free run.

    • cites [424] Castellani, R. J. et al. CD3 in Lewy pathology: does the abnormal recall of neurodevelopmental processes underlie Parkinson’s disease. J. Neural Transm. (Vienna) 118, 23–26 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunosuppression with FK506 significantly decreased tau pathology and increased lifespan in young P301S Tg mice, demonstrating that microglial activation and neuroinflammation promoted the early progression of tauopathies.

    “Importantly, immunosuppression with FK506 significantly decreased tau pathology and increased lifespan in young P301S Tg mice, thereby demonstrating that microglial activation and neuroinflammation promoted the early progression of tauopathies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [395] Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The vast majority of studies found that DLB patients and non-demented controls had similar microglial activation and neuroinflammation levels, except two studies that examined only 5 cases of DLB each.

    “the vast majority of these studies found that DLB patients and non-demented controls had similar microglial activation and neuroinflammation levels,416–420 except two studies that examined only 5 cases of DLB each.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [416] Shepherd, C. E., Thiel, E., McCann, H., Harding, A. J. & Halliday, G. M. Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies. Arch. Neurol. 57, 817–822 (2000). source

      Not checked in the free run.

    • cites [417] Streit, W. J. & Xue, Q. S. Microglia in dementia with Lewy bodies. Brain Behav. Immun. 55, 191–201 (2016). source

      Not checked in the free run.

    • cites [418] Bachstetter, A. D. et al. Disease-related microglia heterogeneity in the hippocampus of Alzheimer’s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol. Commun. 3, 32 (2015). source

      Not checked in the free run.

    • cites [419] Erskine, D. et al. Molecular changes in the absence of severe pathology in the pulvinar in dementia with Lewy bodies. Mov. Disord. 33, 982–991 (2018). source

      Not checked in the free run.

    • cites [420] Amin, J. et al. Neuroinflammation in dementia with Lewy bodies: a human post-mortem study. Transl. Psychiatry 10, 267 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia could phagocytize different tau species, and this process was partly dependent on the microglial fractalkine receptor CX3CR1.

    “Microglia could phagocytize different tau species,386,387 and this process was partly dependent on microglial fractalkine receptor (CX3CR1) receptor.388”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [386] Majerova, P. et al. Microglia display modest phagocytic capacity for extracellular tau oligomers. J. Neuroinflammation 11, 161 (2014). source

      Not checked in the free run.

    • cites [387] Bolos, M. et al. Direct evidence of internalization of tau by microglia in vitro and in vivo. J. Alzheimers Dis. 50, 77–87 (2016). source

      Not checked in the free run.

    • cites [388] Bolos, M. et al. Absence of CX3CR1 impairs the internalization of Tau by microglia. Mol. Neurodegener. 12, 59 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Senescent glial cells directly contribute to neuronal tau pathology and cognitive impairment.

    “These results show that senescent glial cells directly contribute to neuronal tau pathology and cognitive impairment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A distinctive pattern of microglial activation and tau pathology was found in CBD and PSP, with CBD showing more pathology in supratentorial structures and PSP showing more pathology in infratentorial structures.

    “Although both PSP and CBD brains showed microglial activation, a distinctive pattern of microglial activation and tau pathology was found in CBD and PSP, with CBD showing more pathology in supratentorial structures. In comparison, PSP showed more pathology in infratentorial structures.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [374] Ishizawa, K. & Dickson, D. W. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J. Neuropathol. Exp. Neurol. 60, 647–657 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo PET investigations demonstrated significant microglial activation in affected areas of the HD brain, and this pathological phenomenon is more pronounced in severe cases of HD.

    “In vivo PET investigations have demonstrated significant microglial activation in affected areas of the HD brain, and this pathological phenomenon is more pronounced in severe cases of HD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [442] Politis, M. et al. Microglial activation in regions related to cognitive function predicts disease onset in Huntington’s disease: a multimodal imaging study. Hum. Brain Mapp. 32, 258–270 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    T cell infiltration is involved in the pathological mechanism of tauopathies, although the exact mechanism remains unclear.

    “suggesting that T cell infiltration is involved in the pathological mechanism of tauopathies, although the exact mechanism remains unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Deficiency of CX3CR1 enhanced tau phosphorylation and aggregation and memory impairment in hTau mice.

    “The deficiency of the CX3CR1 enhanced tau phosphorylation and aggregation and memory impairment in a transgenic mouse model of tauopathy in which the WT human MAPT gene replaced the endogenous mouse Mapt gene (hTau mice).389”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [389] Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased microglial activation was found in CBD brains compared with controls, and microglial activation in most regions correlated with tau burden.

    “Similar to PSP, increased microglial activation was also found in CBD brains compared with controls, and that microglial activation in most regions correlated with tau burden.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [374] Ishizawa, K. & Dickson, D. W. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J. Neuropathol. Exp. Neurol. 60, 647–657 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A C1q-blocking antibody could inhibit microglial synapse removal and rescue synapse density in cultured neurons and Tau-P301S mice.

    “A C1q-blocking antibody could inhibit microglial synapse removal and rescue synapse density in cultured neurons and Tau-P301S mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [390] Dejanovic, B. et al. Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron 100, 1322–1336.e1327 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia are activated when live neurons with tau aggregation expose phosphatidylserines as an eat-me signal; this is followed by opsonin MFGE8 and nitric oxide released from microglia, resulting in engulfment of the live neuron by microglia.

    “Mechanically, microglia are activated when live neurons with tau aggregation expose phosphatidylserines as a “eat-me” signal. This is followed by opsonin milk-fat-globule EGF-factor-8 (MFGE8) and nitric oxide released from the microglia, resulting in the engulfment of the live neuron by the microglia.391”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [391] Brelstaff, J., Tolkovsky, A. M., Ghetti, B., Goedert, M. & Spillantini, M. G. Living neurons with tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia. Cell Rep. 24, 1939–1948.e1934 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An MPO inhibitor, when applied in the MSA mouse model in the early stage of the disease, suppressed microglial activation and neuroinflammation, reduced intracellular aggregates of α-syn, and rescued neuronal loss and improved motor deficits.

    “An MPO inhibitor, when applied in the MSA mouse model in the early stage of the disease, suppressed microglial activation and neuroinflammation, reduced intracellular aggregates of α-syn, and rescued neuronal loss and improved motor deficits.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [495] Stefanova, N., Georgievska, B., Eriksson, H., Poewe, W. & Wenning, G. K. Myeloperoxidase inhibition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Neurotox. Res. 21, 393–404 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The timing of treatment is important, and inhibition of microglial activation should be implemented early in the disease.

    “suggesting that the timing of treatment is important, and that inhibition of microglial activation should be implemented early in the disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AD patients and mouse models have elevated levels of inflammatory markers, and several AD risk genes associated with innate immune function have been identified, suggesting that neuroinflammation plays a critical role in AD pathogenesis.

    “AD patients and mouse models have elevated levels of inflammatory markers, and several AD risk genes associated with innate immune function have been identified, suggesting that neuroinflammation plays a critical role in AD pathogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [457] Leng, F. & Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat. Rev. Neurol. 17, 157–172 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Minocycline can cross the blood-brain barrier and inhibit microglial activation and pro-inflammatory cytokines production.

    “Minocycline belongs to second‐generation tetracyclines, which can cross the blood‐brain barrier and inhibit microglial activation and pro‐inflammatory cytokines production.497–499”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [497] Kobayashi, K. et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 4, e525 (2013). source

      Not checked in the free run.

    • cites [498] Moller, T. et al. Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. Glia 64, 1788–1794 (2016). source

      Not checked in the free run.

    • cites [499] Tikka, T., Fiebich, B. L., Goldsteins, G., Keinanen, R. & Koistinaho, J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J. Neurosci. 21, 2580–2588 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of NF-κB activation by daily oral administration of BANA reduced reactive microglia and prolonged survival in SOD1G93A rats.

    “Another study also demonstrated that inhibition of NF-κB activation by daily oral administration of A Nitroalkene Benzoic Acid Derivative (BANA) could reduce reactive microglia and prolong survival in SOD1G93A rats.505”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [505] Ibarburu, S. et al. A nitroalkene benzoic acid derivative targets reactive microglia and prolongs survival in an inherited model of ALS via NF-kappaB inhibition. Neurotherapeutics 18, 309–325 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLRP3 inhibitor MCC950 significantly inhibited inflammasome activation, accumulation of α-synuclein aggregates, and nigrostriatal dopaminergic degeneration, improving motor performance in PD mouse models.

    “Additionally, NLRP3 inhibitor MCC950 significantly inhibited inflammasome activation, accumulation of α-synuclein aggregates, and nigrostriatal dopaminergic degeneration, improving motor performance in PD mouse models.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [223] Gordon, R. et al. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med. 10, eaah4066 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In transgenic MSA mouse model, minocycline suppressed microglial activation and prevented loss of dopaminergic substantia nigra pars compacta neurons and striatal dopaminergic terminals.

    “When applied in the transgenic MSA mouse model, minocycline suppressed microglial activation and prevented loss of dopaminergic substantia nigra pars compacta neurons and striatal dopaminergic terminals.276”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [276] Stefanova, N. et al. Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy. Mov. Disord. 22, 2196–2203 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MPO is a key enzyme that produces ROS by phagocytic cells such as microglia and is a mediator of inflammatory processes in many diseases.

    “Myeloperoxidase (MPO) is a key enzyme that produces ROS by phagocytic cells such as microglia and is a mediator of inflammatory processes in many diseases.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [490] Aratani, Y. Myeloperoxidase: Its role for host defense, inflammation, and neutrophil function. Arch. Biochem. Biophys. 640, 47–52 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exenatide provided both motor and cognitive benefits in PD patients and was well tolerated.

    “Exenatide, one of the most extensively studied GLP-1 receptor agonists, provided both motor and cognitive benefits in PD patients and was well tolerated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [493] Aviles-Olmos, I. et al. Exenatide and the treatment of patients with Parkinson’s disease. J. Clin. Invest. 123, 2730–2736 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Progranulin reduction in microglia alone is sufficient to recapitulate inflammation and lysosomal dysfunction, both of which are important pathogenic drivers in FTD-GRN.

    “Progranulin reduction in microglia alone is sufficient to recapitulate inflammation, and lysosomal dysfunction, both of which are important pathogenic drivers in FTD-GRN.510”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [510] Telpoukhovskaia, M. A. et al. Discovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in progranulin-deficient microglia. Sci. Rep. 10, 13688 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pathological proteins of ALS can be secreted into the extracellular matrix, and these pathological proteins are sensed by microglia, causing microglial activation and pro-inflammatory effect that are harmful to co-cultured motor neurons.

    “Additionally, pathological proteins of ALS can be secreted into the extracellular matrix, and these pathological proteins are sensed by microglia, causing microglial activation and pro-inflammatory effect that are harmful to co-cultured motor neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [507] Zhao, W. et al. Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia 58, 231–243 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fluoxetine significantly reduces LPS-induced pro-inflammatory cytokines production and oxidative stress in microglia and enhances microglia phagocytosis and autophagy.

    “Besides, Fluoxetine, a selective serotonin reuptake inhibitor, significantly reduces LPS-induced pro-inflammatory cytokines production and oxidative stress in microglia and enhances microglia phagocytosis and autophagy.501”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [501] Park, S. H., Lee, Y. S., Yang, H. J. & Song, G. J. Fluoxetine potentiates phagocytosis and autophagy in microglia. Front. Pharmacol. 12, 770610 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LPS-treated mSOD1G93A microglia caused microglial activation and released nitric oxide, which induced co-cultured motor neuron injury.

    “In addition, LPS-treated mSOD1G93A microglia caused microglial activation and released nitric oxide, which induced co-cultured motor neuron injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [506] Xiao, Q. et al. Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia. J. Neurochem. 102, 2008–2019 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MPO inhibitor therapy initiated in the advanced stage of the disease after the onset of severe MSA-like neuropathology reduced microglial activation and decreased α-syn accumulation in degenerating brain areas, but failed to improve motor impairments and rescue neuronal loss.

    “In the following study, MPO inhibitor therapy was initiated in the advanced stage of the disease after the onset of severe MSA-like neuropathology. It reduced microglial activation and decreased α-syn accumulation in degenerating brain areas. However, these effects failed to improve motor impairments and rescue neuronal loss,496”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [496] Kaindlstorfer, C. et al. Failure of neuroprotection despite microglial suppression by delayed-start myeloperoxidase inhibition in a model of advanced multiple system atrophy: clinical implications. Neurotox. Res. 28, 185–194 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial elimination in R6/2 mice prevented the loss of PNNs and dramatically increased PNNs in the brains of naïve littermates.

    “Microglial elimination in R6/2 mice prevented the loss of PNNs and dramatically increased PNNs in the brains of naïve littermates.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [456] Crapser, J. D. et al. Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington’s disease. Brain 143, 266–288 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 activation increased Aβ phagocytosis, relieved neuroinflammation, and improved cognitive behavior in AD mouse models.

    “Emerging evidence has shown that TREM2 activation increased Aβ phagocytosis, relieved neuroinflammation, and improved cognitive behavior in AD mouse models.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [171] Schlepckow, K. et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol. Med. 12, e11227 (2020). source

      Not checked in the free run.

    • cites [172] Wang, S. et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J. Exp. Med. 217, e20200785 (2020). source

      Not checked in the free run.

    • cites [173] Zhao, P. et al. A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease. Sci. Transl. Med. 14, eabq0095 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DPDS improved motor deficit, prolonged survival, and reduced motor neuronal loss in hSOD1G93A transgenic mouse through suppressing microglia activation by inhibiting NLRP3 inflammasome activation and IΚb/NF-κB pathway.

    “For example, the organoselenium compound diphenyl diselenide (DPDS) improved motor deficit, prolonged survival, and reduced motor neuronal loss in hSOD1G93A transgenic mouse through suppressing microglia activation by inhibiting NLRP3 inflammasome activation and IΚb/NF-κB pathway.504”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [504] Zhang, C. et al. Diphenyl diselenide protects motor neurons through inhibition of microglia-mediated inflammatory injury in amyotrophic lateral sclerosis. Pharmacol. Res. 165, 105457 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fluoxetine ameliorated motor deficits and decreased neurodegenerative pathology in MSA mice.

    “Fluoxetine ameliorated motor deficits and decreased neurodegenerative pathology in MSA mice.502”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [502] Ubhi, K. et al. Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of alpha-synucleinopathy. Exp. Neurol. 234, 405–416 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Controlling microglia fate towards a beneficial phenotype is feasible and worth exploring to treat AD.

    “The above studies suggest that controlling microglia fate towards a beneficial phenotype is feasible and worth exploring to treat AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pharmacologic blockade of P2RX7 at an early stage in tau mice significantly impaired exosome secretion from microglia, decreased tau accumulation in the brain, and improved working and contextual memory.

    “Pharmacologic blockade of P2RX7 at an early stage in tau mice significantly impaired exosome secretion from microglia, decreased tau accumulation in the brain, and improved working and contextual memory.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Ruan, Z. et al. P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice. Mol. Neurodegener. 15, 47 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the CNS, microglia express the highest progranulin levels and show higher expression in reactive states when responding to aging or disease pathology.

    “In the CNS, microglia express the highest progranulin levels and show higher expression in reactive states when responding to aging,360 or disease pathology.509”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [360] Zhang, J. et al. Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature 588, 459–465 (2020). source

      Not checked in the free run.

    • cites [509] Chen-Plotkin, A. S. et al. Brain progranulin expression in GRN-associated frontotemporal lobar degeneration. Acta Neuropathol. 119, 111–122 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AZD3241, a selective and irreversible MPO inhibitor, reduced microglial activation assessed by PET imaging in PD patients and was well tolerated.

    “AZD3241, a selective and irreversible MPO inhibitor, reduced microglial activation assessed by PET imaging in PD patients and was well tolerated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [491] Jucaite, A. et al. Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson’s disease. Brain 138, 2687–2700 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Soluble mHTT activates IκB Kinase (IKK), triggering the NF-kB signaling pathway and leading to increased gene expression of pro-inflammatory cytokines.

    “It has been shown that soluble mHTT activate IκB Kinase (IKK), triggering the NF-kB signaling pathway,446 and leads to the increase in the gene expression of pro-inflammatory cytokines.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [446] Khoshnan, A. et al. Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity. J. Neurosci. 24, 7999–8008 (2004). source

      Not checked in the free run.

    • cites [447] Hacker, H. & Karin, M. Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006, re13 (2006). source

      Not checked in the free run.

    • cites [448] Khoshnan, A. & Patterson, P. H. The role of IkappaB kinase complex in the neurobiology of Huntington’s disease. Neurobiol. Dis. 43, 305–311 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The HTT-targeting ASO IONIS-HTTRx has completed a Phase 1/2a clinical trial and is currently undergoing a large multicenter worldwide efficacy study.

    “The HTT-targeting ASO IONIS-HTTRx (also known as ISIS 443139 and RG6042), which is thought to act through the RNase H1 mechanism, has completed a Phase 1/2a clinical trial (NCT02519036, NCT03342053) and is currently undergoing a large multicenter worldwide efficacy study.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites NCT02519036

      Not checked in the free run.

    • cites NCT03342053

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a traumatic brain injury mouse model, administration of a PARP inhibitor for 12 days reduced inflammation, increased neuronal survival, and improved performance.

    “In a traumatic brain injury mouse model, administration of a PARP inhibitor for 12 days reduced inflammation, increased neuronal survival, and improved performance.524”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [524] d’Avila, J. C. et al. Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J. Neuroinflammation 9, 31 (2012). source

      Not checked in the free run.

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

    Interpretationnone given

    Modulating neuroinflammation is the most widely used therapeutic strategy.

    “Among these, modulating neuroinflammation is the most widely used therapeutic strategy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Upregulation of Gal3 in microglia occurred prior to onset of motor impairment and contributed to inflammation through NF-κB- and NLRP3 inflammasome-dependent pathways.

    “Its upregulation in microglia occurred prior to the onset of motor impairment and contributed to inflammation through NF-κB- and NLRP3 inflammasome-dependent pathways.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [522] Siew, J. J. et al. Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease. Nat. Commun. 10, 3473 (2019). source

      Not checked in the free run.

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

    Interpretationnone given

    Microglial heterogeneity and dynamics during the progression of disease still need to be better clarified.

    “In spite of significant advances in the understanding of microglial functions in neurodegenerative diseases in recent years, microglial heterogeneity and dynamics during the progression of disease still need to be better clarified.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Knockdown of Gal3 suppressed neuroinflammation, reduced aggregation of mHTT, alleviated motor dysfunction, and increased survival in HD mice.

    “Knockdown of Gal3 suppressed neuroinflammation, reduced the aggregation of mHTT, alleviated motor dysfunction, and increased survival in HD mice.522”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [522] Siew, J. J. et al. Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease. Nat. Commun. 10, 3473 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Administration of 5-LO blocker at both early (3 months) and late (12 months) stages showed a beneficial effect in transgenic tau mice, suggesting inhibition of 5-LO has a protective effect throughout the disease course.

    “It is worth mentioning that administration of 5-LO blocker at both early (age of 3 months)516 and late (age of 12 months)517 stages showed a beneficial effect in the transgenic tau mice, which suggests that the inhibition of 5-LO has a protective effect throughout the disease course.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [516] Giannopoulos, P. F., Chiu, J. & Pratico, D. Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice. Aging Cell 17, e12759 (2018). source

      Not checked in the free run.

    • cites [517] Giannopoulos, P. F., Chiu, J. & Pratico, D. Learning impairments, memory deficits, and neuropathology in aged tau transgenic mice are dependent on leukotrienes biosynthesis: role of the cdk5 kinase pathway. Mol. Neurobiol. 56, 1211–1220 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic ablation of CB2 receptors in R6/2 mice enhanced microglial activation, aggravated disease symptoms, and reduced lifespan.

    “Genetic ablation of CB2 receptors in R6/2 mice enhanced microglial activation, aggravated disease symptoms, and reduced lifespan.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [452] Palazuelos, J. et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132, 3152–3164 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BFT reduced phosphorylated tau levels, ameliorated Aβ load, and improved cognitive function in an AD mouse model APP/PS1 mice.

    “One previous study found that BFT reduced phosphorylated tau levels, ameliorated Aβ load, and improved cognitive function in an AD mouse model APP/PS1 mice.519”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [519] Pan, X. et al. Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain 133, 1342–1351 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the YAC128 transgenic HD mouse model, treatment with an anti-SEMA4D monoclonal antibody reduced brain atrophy, improved cognition, and reduced anxiety-like behavior.

    “In the YAC128 transgenic HD mouse model, treatment with an anti-SEMA4D monoclonal antibody reduced brain atrophy, improved cognition, and reduced anxiety-like behavior.528”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [528] Southwell, A. L. et al. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol. Dis. 76, 46–56 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Galectin-3 (Gal3) is upregulated in the plasma and brain of patients and mice with HD, and plasma Gal3 levels correlated with disease severity.

    “Galectin-3 (Gal3) is a lectin that was upregulated in the plasma and brain of patients and mice with HD, and their plasma Gal3 levels correlated with disease severity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [522] Siew, J. J. et al. Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease. Nat. Commun. 10, 3473 (2019). source

      Not checked in the free run.

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

    Interpretationnone given

    High throughput omic data analyses help identify and determine the functional roles of microglia that are in specific states.

    “The recent advent of high throughput omic data analyses help identify and determine the functional roles of microglia that are in specific states.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Genetic deletion of 5-LO in P301S tau mice or pharmacologic inhibition of 5-LO with zileuton resulted in significant reduction of tau phosphorylation and glial cell activation and ameliorated cognitive deficits.

    “In contrast, genetic deletion of 5-LO in P301S tau mice515 or pharmacologic inhibition of 5-LO with zileuton,512,516,517 both resulted in significant reduction of tau phosphorylation and glial cell activation and thus ameliorated cognitive deficits.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [515] Vagnozzi, A. N., Giannopoulos, P. F. & Pratico, D. The direct role of 5-lipoxygenase on tau pathology, synaptic integrity and cognition in a mouse model of tauopathy. Transl. Psychiatry 7, 1288 (2017). source

      Not checked in the free run.

    • cites [512] Giannopoulos, P. F. et al. Pharmacologic inhibition of 5-lipoxygenase improves memory, rescues synaptic dysfunction, and ameliorates tau pathology in a transgenic model of tauopathy. Biol. Psychiatry 78, 693–701 (2015). source

      Not checked in the free run.

    • cites [516] Giannopoulos, P. F., Chiu, J. & Pratico, D. Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice. Aging Cell 17, e12759 (2018). source

      Not checked in the free run.

    • cites [517] Giannopoulos, P. F., Chiu, J. & Pratico, D. Learning impairments, memory deficits, and neuropathology in aged tau transgenic mice are dependent on leukotrienes biosynthesis: role of the cdk5 kinase pathway. Mol. Neurobiol. 56, 1211–1220 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial activation in HD is caused by neuronal mHTT-mediated excitotoxicity or mHTT expression in microglia.

    “Microglial activation in HD is caused by neuronal mHTT-mediated excitotoxicity or mHTT expression in microglia.529”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [529] Yang, H. M., Yang, S., Huang, S. S., Tang, B. S. & Guo, J. F. Microglial activation in the pathogenesis of Huntington’s disease. Front. Aging Neurosci. 9, 193 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Reducing the expression of mutant huntingtin RNA (Htt RNA) could potentially attenuate microglial activation, alleviate inflammatory processes, and provide neuroprotection.

    “Several therapeutic approaches are being investigated to reduce the expression of mutant huntingtin RNA (Htt RNA), which could potentially attenuate microglial activation, alleviate inflammatory processes, and provide neuroprotection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Olaparib, a PARP-1 inhibitor, has a neuroprotective effect in the R6/2 mouse model of HD; administering from pre-symptomatic stage increased survival and improved clinical outcomes mainly by modulating inflammasome activation.

    “Olaparib, a PARP-1 inhibitor commercially available as an anti-neoplastic drug, was found to have a neuroprotective effect in the R6/2 mouse model of HD. Administering Olaparib from the pre-symptomatic stage increased survival and improved clinical outcomes mainly by modulating the inflammasome activation.525”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [525] Paldino, E. et al. Modulation of Inflammasome and Pyroptosis by Olaparib, a PARP-1 Inhibitor, in the R6/2 Mouse Model of Huntington’s Disease. Cells 9, 2286 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Regulation of neuroinflammation, inhibition of microglial exosome synthesis and secretion, altering microglial metabolism, altering the microglial phenotype, and TREM2 activation are potential therapeutic strategies in treating neurodegenerative diseases.

    “Regulation of neuroinflammation, inhibition of microglial exosome synthesis and secretion, altering microglial metabolism, altering the microglial phenotype, and TREM2 activation are potential therapeutic strategies in treating neurodegenerative diseases.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Dysfunctional microglia may also promote the clearance of synapses and perineuronal nets and impair neuronal plasticity and activity.

    “Dysfunctional microglia may also promote the clearance of synapses and perineuronal nets and impair neuronal plasticity and activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    5-LO is broadly expressed in the CNS and is a potent pro-inflammatory mediator regulating microglial activation.

    “5-lipoxygenase (5-LO), broadly expressed in the CNS, is a potent pro-inflammatory mediator regulating microglial activation.511”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [511] Zhang, X. Y. et al. Regulation of rotenone-induced microglial activation by 5-lipoxygenase and cysteinyl leukotriene receptor 1. Brain Res. 1572, 59–71 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In progranulin-deficient primary mouse microglia, nor-BNI and DB-cAMP promoted microglial transcriptional profiles transition from Grn KO signature toward Grn WT state and partially rescued lysosomal dysfunction.

    “Experimental evidence revealed that in progranulin‑deficient primary mouse microglia, these two compounds promoted microglial transcriptional profiles transition from the Grn KO signature toward the Grn WT state and could also partially rescue lysosomal dysfunction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [510] Telpoukhovskaia, M. A. et al. Discovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in progranulin-deficient microglia. Sci. Rep. 10, 13688 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Microglia can limit the propagation of Aβ and tau by phagocytosis of these proteins, but can also contribute to neurodegeneration by accelerating their spreading.

    “Microglia can limit the propagation of Aβ and tau by phagocytosis of these proteins, but it can also contribute to neurodegeneration by accelerating their spreading.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Over-expression of 5-LO in the brain of a transgenic model of human tauopathy increased tau phosphorylation and glial activation and enhanced behavioral impairments.

    “By employing an AAV vector system to over-express 5-LO in the brain of the same transgenic model of human tauopathy, 5-LO increased tau phosphorylation and glial activation and enhanced behavioral impairments.513,514”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [513] Giannopoulos, P. F. & Pratico, D. Overexpression of 5-Lipoxygenase Worsens the Phenotype of a Mouse Model of Tauopathy. Mol. Neurobiol. 55, 5926–5936 (2018). source

      Not checked in the free run.

    • cites [514] Vagnozzi, A. N., Giannopoulos, P. F. & Pratico, D. Brain 5-lipoxygenase over-expression worsens memory, synaptic integrity, and tau pathology in the P301S mice. Aging Cell 17, e12695 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysregulation of microglia may cause impaired phagocytosis of pathological deposits, pathological deposits propagation, neuroinflammation, and microglial phenotype switching, and thus lead to pathology progression and neurodegeneration.

    “Dysregulation of microglia may cause impaired phagocytosis of pathological deposits, pathological deposits propagation, neuroinflammation, and microglial phenotype switching, and thus lead to pathology progression and neurodegeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IONIS-HTTRx therapy has been deemed safe, with no significant side effects reported in the treatment group.

    “This therapy has been deemed safe, with no significant side effects reported in the treatment group.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [530] Tabrizi, S. J. et al. Targeting huntingtin expression in patients with Huntington’s disease. N. Engl. J. Med. 380, 2307–2316 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two selective ASOs, WVE-120101 and WVE-120102, targeting SNPs in HD patients, have been investigated in human studies; results showed no significant change in mHTT protein in CSF.

    “Two selective ASOs, WVE-120101 and WVE-120102, which target the most often occurring SNPs in HD patients, have been investigated in human studies (NCT04617847, NCT04617860). However, results showed no significant change in mHTT protein in CSF.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites NCT04617847

      Not checked in the free run.

    • cites NCT04617860

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of CB2 receptors with selective agonists reduced neuroinflammation, striatal neuronal loss, and motor symptoms in WT mice subjected to excitotoxicity.

    “In contrast, activation of CB2 receptors with selective agonists reduced neuroinflammation, striatal neuronal loss, and motor symptoms in WT mice subjected to excitotoxicity.452”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [452] Palazuelos, J. et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132, 3152–3164 (2009). source

      Not checked in the free run.

204 of 204

  • The authors state this as an assumption.

    The M1/M2 and A1/A2 classifications, although inaccurate, are helpful for elucidating microglia-astrocyte interaction.

    “Although the canonical M1/M2 (microglia) and A1/A2 (astrocyte) classifications are not accurate in describing the states of microglia and astrocytes, this classification is helpful to elucidate the interaction of microglia and astrocytes and will be adopted here.”

  • The paper relies on this without support.

    Increases in TSPO-PET ligand binding in AD and PD brains reflect microglial activation.

    “Consistent evidence using PET imaging indicated microglial activation in the brains of AD patients.”
    “Additionally, PET scans of PD patients revealed widespread microglial activation.”

  • The paper relies on this without support.

    Findings from animal models of neurodegenerative diseases can be extrapolated to human disease mechanisms.

    “Transgenetic mouse models of MSA overexpressing α-syn in oligodendrocytes also presented early and significant microglial activation and related neuroinflammation accompanying the α-syn accumulation in oligodendrocytes.292,293”

  • The paper relies on this without support.

    Findings from animal models of neurodegenerative diseases are relevant to human disease.

    “These findings suggest that modulation of microglial bioenergetic pathways and metabolic state might be promising strategies to treat AD.”

  • The paper relies on this without support.

    Microglial activation observed by PET or immunohistochemistry reflects functional microglial state.

    “In vivo brain imaging allows the investigation of inflammatory processes in the early stages of the disease and facilitates longitudinal monitoring of microglial activation during disease progression.”

  • The paper relies on this without support.

    Modulating microglial phenotype or reducing neuroinflammation will be safe and effective in humans.

    “The above evidence suggests that modulating microglia-mediated neuroinflammation is a key therapeutic target in treating AD.”

  • The paper relies on this without support.

    The M1/M2 polarization classification is valid and meaningful for microglia.

    “Furthermore, stimulation of CB1 and/or CB2 receptors in microglia was demonstrated to induce M2 polarization, while knocking out CB2 receptors in mice inhibited M2 polarization.”

  • The paper relies on this without support.

    Exosome-mediated tau propagation is a significant mechanism in human tauopathies.

    “Overall, microglia and their secreted exosomes contribute to tauopathy progression and the inhibition of exosome synthesis or secretion could be a therapeutic target.”

  • The paper relies on this without support.

    Heterozygous GRN mutations cause progranulin haploinsufficiency, resulting in patients with FTD (FTD-GRN).

    “Heterozygous GRN mutations cause progranulin haploinsufficiency, resulting in patients with FTD (FTD-GRN).”

  • The paper relies on this without support.

    GRN encodes a secreted protein (progranulin) expressed in microglia and neurons in human brains.

    “GRN encodes a secreted protein (progranulin) expressed in microglia and neurons in human brains.”

  • The paper relies on this without support.

    There is no disease-modifying therapy for HD, so current treatment focuses on chorea and mental symptoms.

    “There is no disease-modifying therapy for HD, so current treatment focuses on chorea and mental symptoms.”

  • The paper relies on this without support.

    GWAS have demonstrated that most AD risk genes were highly or exclusively in microglia.

    “Recently, GWAS have demonstrated that most AD risk genes were highly or exclusively in microglia, suggesting that microglia play an important role in the development of AD.”
12 of 12

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?

  • When microglia become dysfunctional, they can release inflammatory factors that damage neurons and synapses, ultimately contributing to disease pathogenesis.

    “However, when microglia become dysfunctional, they can release inflammatory factors that damage neurons and synapses, ultimately contributing to disease pathogenesis [11].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [11]

    The Parkinson’s disease and ALS/FTD sections describe inflammatory cytokines released by activated microglia and microglia-mediated inflammation that injures neurons. The homeostasis section and Conclusion also link dysfunctional microglia to synapse loss and disease progression, but attribute synapse loss chiefly to aberrant elimination or clearance rather than showing that the released inflammatory factors damage synapses. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Perturbations in microglial activity, often associated with aging, can affect the effective clearance of neuron-derived Aβ fibrils, leading to increased plaque formation and progression of cognitive and behavioral impairments.

    “However, perturbations in microglial activity, often associated with aging, can affect the effective clearance of these neuron-derived Aβ fibrils, leading to increased plaque formation and the progression of cognitive and behavioral impairments (17–20).”

    From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [17]

    In “Effect of microglia on Aβ pathology” (page unavailable), the review says aging-related increases in microglial NgR impair Aβ clearance, while NgR-deficient AD mice have lower amyloid burden and improved cognition. This supports the main relationship, but the passage does not identify the cleared Aβ as neuron-derived fibrils or establish progression of behavioral impairments. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Prior work shows that E4 impairs microglial metabolism/immune reactivity and can exaggerate cytokine reactivity to LPS.

    “Prior work shows that E4 impairs microglial metabolism/immune reactivity and can exaggerate cytokine reactivity to LPS”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Gao et al., 2023

    In the Alzheimer’s disease section (page unavailable), Fig. 2 describes altered metabolism in APOE4-bearing microglia, and the text reports slower migration toward Aβ and less Aβ uptake with APOE4 than with APOE3. Those findings support altered metabolism and aspects of microglial function, but the passages do not link APOE4 to exaggerated cytokine reactivity after LPS stimulation. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Microglia contribute crucially to brain homeostasis during aging and neurodegeneration.

    “Numerous studies have highlighted the crucial contribution of microglia to brain homeostasis during aging and neurodegeneration (17, 18, 28, 30).”

    From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [17]

  • Pharmacological targeting of metabolic pathways to modulate microglial activation has shown promise in preclinical studies.

    “Similarly, pharmacological targeting of metabolic pathways to modulate microglial activation has shown promise in preclinical studies (Amo-Aparicio et al., 2024; Gao et al., 2023; Lepiarz-Raba et al., 2023).”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Gao et al., 2023

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.

  • Microglia are said to arise solely from primary EMPs, but a second-wave origin is also described

    Major

    The ontogeny section concludes that all microglia arise from primary erythromyeloid precursors (EMPs). The next section describes Hoxb8 microglial progenitors arising during the second wave of yolk-sac hematopoiesis and contributing to adult microglia.

1 of 1

Cites

4 retracted

Flagged first, then by citations

Research works printed but not linked: 4

  1. Rı´o-Hortega, P. El “Tercer Elemento” de los Centros Nerviosos. I. La Microglı´a en Estado Normal, Boletı´n de la Sociedad Espan˜ola de Biologı´a VIII, pp. 67–82, (in Spanish). (1919).
  2. Rı´o-Hortega, P. El “Tercer Elemento de los Centros Nerviosos”. II. Intervencio´n de la Microglı´a en los Procesos Patolo´gicos (Ce´lulas en Bastoncitoy Cuerpos Gra´nuloadiposos), Boletı´n de la Sociedad Espan˜ ola de Biologı´a VIII, pp. 91–103, (in Spanish). (1919).
  3. Rı´o-Hortega, P. El “Tercer Elemento” de los Centros Nerviosos. III. Naturaleza Probable de la Microglı´a, Boletı´n de la Sociedad Espan˜ ola de Biologı´a VIII, pp. 108–121, (in Spanish). (1919).
  4. Rı´o-Hortega, P. El “Tercer Elemento de los Centros Nerviosos”. IV. Poder Fagocitarioy Movilidad de la Microglı´a, Boletı´n de la Sociedad Espan˜ ola de Biologı´a VIII, pp. 154–171, in Spanish. (1919).

Cited by

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Related

Authors
Gao, C., Jiang, J., Tan, Y., & Chen, S.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
  • Tan, Yuyan
  • Chen, Shengdi
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-09-22
Volume
8
Issue
1
Pages
359-359
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-023-01588-0
PMC
PMC10514343
OpenAlex
W4386913845
Semantic Scholar
6232709d2c4c65345a5d72e7e13f5f923c50302f
Cited by
1,616
References
556
Citations by year
2026: 656 · 2025: 672 · 2024: 280 · 2023: 8
FWCI
42.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (2017-01-07-00-01-E00046, 2018SHZDZX05, 81971183, 201701, 82101477, 81971187, 82171401)
  • Shanghai Municipal Education Commission (2017-01-07-00-01-E00046, 81971187, 2018SHZDZX05)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
microglia, neurodegenerative diseases, microglial activation, microglial heterogeneity, phagocytosis, protein aggregate clearance, neuroinflammation, peripheral immune cell infiltration, extracellular vesicles, autophagy, microglia-targeted therapy, Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, Huntington's disease
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Animals, Microglia, Neurodegenerative Diseases, Protein Aggregates

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.

Statistics and arithmetic are recomputed, not judged.

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

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

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