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Cited by 1,710Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsInflammasome and immune disorders

Microglia in neurodegeneration

Open access
Hickman, Suzanne, Izzy, Saef, Sen, Pritha, Morsett, Liza, El Khoury, Joseph·2018·Nature Neuroscience
DOI 10.1038/s41593-018-0242-xPMC PMC6817969
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Abstract

The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection. Microglia use a defined armamentarium of genes to perform these tasks. In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons. Injury to neurons in Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation. Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli. Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury. Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy. Microglia are the sentinels, housekeepers, and defenders of the brain. In this review we consider the immune checkpoints that control microglial functions and discuss how their imbalance and subsequent neuroinflammation leads to neurodegeneration.

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Crossref · 10.1038/s41593-018-0242-x

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  • Premisecitation

    RNA-seq identified microglia-specific markers in healthy brain including HexB, P2ry12, S100A8, S100A9, Tmem119, Gpr34, SiglecH, TREM2, and Olfml3.

    “RNA-seq analysis identified a new set of microglia-specific markers in the healthy brain that include HexB, P2ry12, S100A8, S100A9, Tmem119, Gpr34, SiglecH, TREM2, and Olfml37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). source

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  • Premisecitation

    Trem2 mutations are associated with a 3.0- to 4.5-fold increased AD risk, almost as high as that associated with ApoE ε4.

    “Mutations in triggering receptor expressed on myeloid cells 2 (Trem2) were associated with a 3.0- to 4.5-fold increased AD risk, almost as high as that associated with ApoE ε434,35.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013). source

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    • cites [35] Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013). source

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  • Interpretationreasoning

    Dysregulation of microglial functions creates an imbalance that initiates or propagates neurodegeneration.

    “Dysregulation of any of these functions results in an imbalance that initiates or propagates neurodegeneration.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Sensing is a prerequisite for microglial housekeeping and host defense functions.

    “Sensing is a prerequisite for microglia to perform their housekeeping and host defense functions.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Microglia form a network that spans the CNS.

    “Microglia form a network spanning the CNS9.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Lawson, L. J., Perry, V. H., Dri, P. & Gordon, S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151–170 (1990). source

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    Premisecitation

    Microglia make up 5-12% of CNS cells, with the proportion varying by region.

    “Microglia constitute 5–12% of CNS cells, depending on the region9.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Lawson, L. J., Perry, V. H., Dri, P. & Gordon, S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151–170 (1990). source

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

    Premisecitation

    Microglia are the principal resident immune cells of the brain and participate in homeostasis and host defense against pathogens and CNS disorders.

    “They are the principal resident immune cells of the brain and are involved in homeostasis and in host defense against pathogens and CNS disorders10,11.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] El Khoury, J. Neurodegeneration and the neuroimmune system. Nat. Med. 16, 1369–1370 (2010). source

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    • cites [11] Ransohoff, R. M. & El Khoury, J. Microglia in health and disease. Cold Spring Harb. Perspect. Biol. 8, a020560 (2015). source

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    Premisecitation

    Microglia are mesenchymal myeloid cells that originate in the yolk sac and can self-renew independently of hematopoietic stem cells.

    “Ontological studies of microglia confirmed Hortega’s suspicion that they are mesenchymal, myeloid12, originating in the yolk sac, and capable of self-renewal independent of hematopoietic stem cells13.”
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    • cites [12] Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013). source

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    • cites [13] Tay, T. L. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803 (2017). source

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    Premisecitation

    Microglial survival and maintenance depend on cytokines including CSF1 and IL-34 and on transcription factors such as IRF8.

    “Microglial survival and maintenance depend on cytokines, including CSF1 and interleukin (IL)-3414, and on transcription factors such as IRF812.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012). source

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    • cites [12] Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013). source

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

    Interpretationown data

    Microglia perform three essential functions: sensing their environment, physiological housekeeping, and protection against injurious self and non-self agents.

    “Microglial transcriptomes allow them to perform three essential functions: (i) sense their environment, (ii) conduct physiological housekeeping, and (iii) protect against modified-self and non-self injurious agents.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Microglial-Aβ interaction is a double-edged sword: sensing Aβ leads to clearance, but persistent Aβ and chronic interaction drive further amyloid deposition.

    “Based on these findings, microglial–Aβ interaction is a double-edged sword. While monitoring the brain environment, microglial sensing of Aβ peptides results in Aβ clearance and removal of the injurious agent (Fig. 3). However, persistent production of Aβ and its chronic interaction with microglia drive further amyloid deposition.”
    Quote in the paperSubstantial claim

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    Premisenone given

    Tauopathies are neurodegenerative diseases characterized by hyperphosphorylated aggregated tau and neurofibrillary tangles.

    “Tauopathies are neurodegenerative diseases characterized by hyperphosphorylated and aggregated tau and neurofibrillary tangles.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Microglial interaction with astrocytes is involved in homeostasis, inflammation, and possibly neurodegeneration.

    “Interacting with astrocytes is another important microglial function involved in homeostasis, inflammation, and possibly neurodegeneration26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). source

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    Premiseown data

    Microglial processes are dynamic, scan the area around the cell body every few hours, and rapidly polarize toward focal injury.

    “Their thin processes are dynamic and in constant motion, allowing them to scan the area surrounding their cell body every few hours and rapidly polarize toward focal injury (Fig. 1a–c and Supplementary Video 1).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Activated proinflammatory microglia increase tau phosphorylation and drive the spread of tau pathology.

    “In contrast, when activated, proinflammatory microglia increase tau phosphorylation50 and drive the spread of tau pathology48.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Lee, D. C. et al. LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J. Neuroinflammation 7, 56 (2010). source

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    • cites [48] Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015). source

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    Premisenone given

    Aβ deposition is regulated by an equilibrium between Aβ production and clearance, and small changes in this equilibrium cause abnormal accumulation.

    “Aβ deposition is regulated by equilibrium between Aβ production and clearance. Small changes in this equilibrium result in abnormal accumulation.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Findings support a direct link between aberrant microglial functions and AD and suggest that a subset of microglia transition from homeostatic to DAMs in AD.

    “These findings support a direct link between aberrant microglial functions and AD and suggest that a subset of microglia transition from a homeostatic to DAMs in AD.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Microglia use nearly 100 genes, their sensome, to detect microenvironment changes; this includes P2yr12, AXL, and MER.

    “They use the products of nearly 100 genes to sense changes in their microenvironment (their sensome) including P2yr12, AXL, and MER4,7,19”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Haynes, S. E. et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci. 9, 1512–1519 (2006). source

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    • cites [7] Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). source

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    • cites [19] Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016). source

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    Premisecitation

    Alzheimer's disease is characterized by Aβ-containing plaques, intracellular hyperphosphorylated tau tangles, and neuronal loss.

    “Alzheimer’s disease (AD) is characterized by formation of Aβ-containing plaques, neurofibrillary tangles comprising intracellular hyperphosphorylated tau protein, and neuronal loss29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016). source

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    Premisecitation

    Microglia-Aβ interactions lead to early synapse loss, production of ROS and RNS, NLRP3 inflammasome activation, and proinflammatory cytokines and TNF.

    “Microglia–Aβ interactions lead to early synapse loss39, production of neurotoxic reactive oxygen and nitrogen species (ROS and RNS), NLRP3 inflammasome activation, and production of proinflammatory cytokines and TNF27,40–42.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [39] Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). source

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    • cites [27] El Khoury, J. B. et al. CD36 mediates the innate host response to beta-amyloid. J. Exp. Med. 197, 1657–1666 (2003). source

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    • cites [40] Coraci, I. S. et al. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am. J. Pathol. 160, 101–112 (2002). source

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    • cites [41] Gold, M. & El Khoury, J. β-amyloid, microglia, and the inflammasome in Alzheimer’s disease. Semin. Immunopathol. 37, 607–611 (2015). source

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    • cites [42] Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355–361 (2017). source

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  • May combine two claims.

    Interpretationown data

    Sensome mRNAs are uniformly expressed across brain areas, suggesting that all microglia can perform sensing.

    “Sensome mRNAs are uniformly expressed in microglia in various areas of the brain, suggesting that all microglia are capable of performing their sensing function (Fig. 1e).”
    Quote in the paperNot a substantial claim

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    Interpretationcitation

    Aβ-induced cytokines promote tau hyperphosphorylation and pathology, creating a self-perpetuating loop that worsens disease.

    “Similarly, Aβ-induced cytokines promote tau hyperphosphorylation and pathology, thus initiating a self-perpetuating loop that culminates in worsening disease44,45.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Oddo, S., Caccamo, A., Kitazawa, M., Tseng, B. P. & LaFerla, F. M. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol. Aging 24, 1063–1070 (2003). source

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    • cites [45] Villemagne, V. L. et al. Aβ-amyloid and tau imaging in dementia. Semin. Nucl. Med. 47, 75–88 (2017). source

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    Premisecitation

    Housekeeping functions include synaptic remodeling, migration to sites of neuronal death for phagocytosis, and maintenance of myelin homeostasis.

    “Physiological housekeeping functions include synaptic remodeling (a function critical for CNS development, homeostasis, and neurodegeneration20–22), migration to sites of neuronal death to phagocytose dead or dying cells23,24 or debris, and maintaining myelin homeostasis25.”
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    • cites [20] Vasek, M. J. et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016). source

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    • cites [21] Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016). source

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    • cites [22] Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014). source

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    • cites [23] Fuhrmann, M. et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat. Neurosci. 13, 411–413 (2010). source

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    • cites [24] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581.e9 (2017). source

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    • cites [25] Healy, L. M. et al. MerTK is a functional regulator of myelin phagocytosis by human myeloid cells. J. Immunol. 196, 3375–3384 (2016). source

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    Premisecitation

    Most tauopathies have neuronal and glial accumulations of toxic insoluble tau, neuronal loss, and proinflammatory microglia.

    “Most tauopathies have neuronal and glial accumulations of toxic insoluble tau, neuronal loss, and proinflammatory microglia47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Ferrer, I. et al. Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J. Neuropathol. Exp. Neurol. 73, 81–97 (2014). source

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    Premisecitation

    DAMs are located around Aβ plaques and have dysregulated expression of sensing, housekeeping, and host-defense genes.

    “DAMs are located around Aβ plaques and have dysregulated expression of sensing, housekeeping, and host-defense genes.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Plaque-associated microglia contain intracellular Aβ, show proinflammatory morphological changes, and have increased proinflammatory markers including MHC II, CD36, IL-1, IL-6, and TNF.

    “They contain intracellular Aβ, suggesting phagocytosis31, show proinflammatory morphological changes such as somatic swelling and process shortening (Fig. 2c), and have increased proinflammatory markers including major histocompatibility complex II, CD36, IL-1, IL-6, and TNF32,33.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31] D’Andrea, M. R., Cole, G. M. & Ard, M. D. The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol. Aging 25, 675–683 (2004). source

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    • cites [32] Tooyama, I., Kimura, H., Akiyama, H. & McGeer, P. L. Reactive microglia express class I and class II major histocompatibility complex antigens in Alzheimer’s disease. Brain Res. 523, 273–280 (1990). source

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    • cites [33] Martin, E., Boucher, C., Fontaine, B. & Delarasse, C. Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer’s disease models: effects of aging and amyloid pathology. Aging Cell 16, 27–38 (2017). source

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    Premisecitation

    Microglia can engulf, degrade, and clear tau.

    “Microglia can engulf, degrade, and clear tau48,49.”
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    • cites [48] Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015). source

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    • cites [49] Bolós, M. et al. Direct evidence of internalization of tau by microglia in vitro and in vivo. J. Alzheimers Dis. 50, 77–87 (2016). source

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    Interpretationcitation

    Proinflammatory microglia precede visible tau pathology in transgenic mice; FK506 attenuates their activation, tau pathology, and extends lifespan, suggesting microglia mediate tau neurotoxicity.

    “Proinflammatory microglia precede visible tau pathology in transgenic mice, and their activation is attenuated by the immunosuppressant drug FK506, which attenuates tau pathology and extends lifespan in these mice, suggesting that microglia can mediate tau neurotoxicity54.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007). source

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    Premisecitation

    Aβ-induced proinflammatory cytokines reduce microglial Aβ clearance, and NLRP3 activation releases ASC that binds Aβ, causing aggregation and seeding or spreading of amyloid pathology.

    “Indeed, Aβ-induced proinflammatory cytokines reduce microglial Aβ clearance ability, and NLRP3 activation releases microglial apoptosis-associated speck-like protein containing a CARD (ASC) which binds Aβ, causing its aggregation and leading to further amyloid ‘seeding’ and spreading of amyloid pathology42.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355–361 (2017). source

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  • May combine two claims.

    Interpretationreasoning

    Persistent neuroinflammation induces neurotoxicity and leads to neurodegeneration.

    “Persistent neuroinflammation in turn induces neurotoxicity, leading to neurodegeneration.”
    Quote in the paperSubstantial claim

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    Premisenone given

    Microglia mediate host defense against infectious pathogens, injurious self-proteins such as Aβ, aggregated α-synuclein, mutant huntingtin, mutant or oxidized SOD, and prions, as well as CNS tumors.

    “Microglia mediate host defense against infectious pathogens, injurious self-proteins such as Aβ, aggregated α-synuclein, mutant huntingtin, mutant or oxidized superoxide dismutase (SOD), or prions, as well as primary or metastatic CNS tumors.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Microglia from Aβ-mice have reduced expression of Aβ-phagocytic receptors and Aβ-degrading enzymes while retaining proinflammatory cytokine production.

    “microglia from a mouse model of Aβ deposition (Aβ-mice) have reduced expression of Aβ-phagocytic receptors and Aβ-degrading enzymes, but their ability to produce proinflammatory cytokines was maintained6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Hickman, S. E., Allison, E. K. & El Khoury, J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 28, 8354–8360 (2008). source

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  • May combine two claims.

    Interpretationreasoning

    There are no resting microglia; most microglia in healthy brains are constantly engaged in sensing, housekeeping, and protecting functions.

    “A take-home message is that there are no resting microglia (Fig. 2). Their sensing, housekeeping, and protecting functions keep them constantly engaged, and most microglia in healthy brains are capable of performing such functions.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Aβ clearance involves microglial phagocytosis and endocytosis via scavenger receptors and extracellular degradation by Aβ-degrading enzymes.

    “Aβ clearance involves, in part36, phagocytosis and endocytosis via microglial scavenger receptors (SRs)37,38 and extracellular degradation by Aβ-degrading enzymes6,36.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [36] El Khoury, J. & Hickman, S.E. Mechanisms of amyloid-beta clearance in Alzheimer’s disease. in Research Progress in Alzheimer’s Disease and Dementia, vol. 4. (ed. Sun, M.-K.) 37–66 (Nova Science Publishers, Hauppauge, NY, USA, 2009).

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    • cites [37] Frenkel, D. et al. Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat. Commun. 4, 2030 (2013). source

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    • cites [38] El Khoury, J. et al. Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382, 716–719 (1996). source

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    • cites [6] Hickman, S. E., Allison, E. K. & El Khoury, J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 28, 8354–8360 (2008). source

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    Premisecitation

    In response to stimuli, microglia can initiate neuroinflammation with cytokines such as TNF and IL-1 and possibly Ccl2, recruiting cells to clear injurious agents and maintain brain homeostasis.

    “In response to such stimuli, microglia can initiate a neuroinflammatory response which, like peripheral inflammation, includes production of cytokines such as TNF and IL-16,27, and possibly chemokines such as Ccl228, to recruit additional cells and induce them to clear injurious agents and maintain brain homeostasis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Hickman, S. E., Allison, E. K. & El Khoury, J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 28, 8354–8360 (2008). source

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    • cites [27] El Khoury, J. B. et al. CD36 mediates the innate host response to beta-amyloid. J. Exp. Med. 197, 1657–1666 (2003). source

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    • cites [28] El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007). source

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    Premisecitation

    PD neurodegeneration occurs in the substantia nigra with dopaminergic denervation of the striatum and Lewy bodies containing aggregated α-synuclein.

    “Neurodegeneration occurs in the substantia nigra, with dopaminergic denervation of the striatum and accumulation of Lewy bodies containing aggregated α-synuclein59.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Dickson, D. W. Neuropathology of Parkinson disease. Parkinsonism Relat. Disord. 46(Suppl 1), S30–S33 (2018). source

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

    Premisecitation

    Parkinson's disease is the second most common neurodegenerative disease, affecting 1.2% of individuals over age 65; most cases are sporadic and 5-10% are inherited.

    “Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting 1.2% of individuals over age 65. Most cases are sporadic and 5–10% are inherited58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Deng, H., Wang, P. & Jankovic, J. The genetics of Parkinson disease. Ageing Res. Rev. 42, 72–85 (2018). source

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    Premisecitation

    At disease onset, microglia promote axonal regeneration, remyelination, clearance of inhibitory myelin debris, and release of neurotrophic factors, suggesting a beneficial role.

    “However, at disease onset, microglia promote axonal regeneration, remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors, suggesting a beneficial role67.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014). source

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    Premisecitation

    Microglia accumulate near α-synuclein deposits and become proinflammatory via receptors that also bind Aβ, such as CD36 and TLR2.

    “Microglia accumulate near α-synuclein deposits and become proinflammatory in a manner dependent on receptors that also bind Aβ, such as CD36 and TLR263–65.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [63] Croisier, E., Moran, L. B., Dexter, D. T., Pearce, R. K. & Graeber, M. B. Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J. Neuroinflammation 2, 14 (2005). source

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    • cites [64] Su, X. et al. Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol. Aging 29, 1690–1701 (2008). source

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    • cites [65] Kim, C. et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4, 1562 (2013). source

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    Premisenone given

    In EAE, microglia release proteases, proinflammatory cytokines, ROS, and RNS, and recruit reactive T lymphocytes, causing toxicity to neurons and oligodendrocyte precursors.

    “In experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, microglia release proteases, proinflammatory cytokines, ROS, and RNS, and they recruit reactive T lymphocytes, thereby causing toxicity to neurons and oligodendrocyte precursors.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Essential microglial functions are altered in EAE and possibly MS, including sensing and clearing debris and mounting a neuroprotective response.

    “What is clear is that essential microglial functions are altered in EAE and possibly in MS, including their ability to sense and clear debris and mount a neuroprotective response.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In Aβ-mice, overexpressing progranulin inhibits Aβ deposition and protects against Aβ toxicity.

    “In Aβ-mice, progranulin overexpression inhibits Aβ deposition and protects from Aβ toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Minami, S. S. et al. Progranulin protects against amyloid β deposition and toxicity in Alzheimer’s disease mouse models. Nat. Med. 20, 1157–1164 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At twelve months, RAGE knockout did not alter cognition or microglial recruitment to plaques.

    “However, no change in cognition or microglial recruitment to plaques was seen in 12-month-old mice”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Vodopivec, I. et al. RAGE does not affect amyloid pathology in transgenic ArcAbeta mice. Neurodegener. Dis. 6, 270–280 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SR-B2 promotes α-synuclein-microglial interactions and detects misfolded mutant or oxidized SOD1 in diseased motor neurons or extracellular space, making these cells proinflammatory.

    “SR-B2 promotes α-synuclein–microglial interactions64 and senses misfolded mutant or oxidized SOD1 in diseased motor neurons or in the extracellular space, rendering these cells proinflammatory85.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Su, X. et al. Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol. Aging 29, 1690–1701 (2008). source

      Not checked in the free run.

    • cites [85] 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.

    Interpretationreasoning

    Blocking CD36- or RAGE-Aβ interactions, or lowering these receptors, may halt or delay AD progression.

    “whereas blocking CD36– or RAGE–Aβ interactions or reducing expression of these SRs may stop or delay AD progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Loss of SR-A1 lowers microglial Aβ uptake by 60% and raises mortality and Aβ accumulation.

    “SR-A1-deficiency decreases microglial Aβ uptake by 60%37,136 and increases mortality and Aβ accumulation37,136”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Frenkel, D. et al. Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat. Commun. 4, 2030 (2013). source

      Not checked in the free run.

    • cites [136] Cornejo, F. et al. Scavenger receptor-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer’s disease pathophysiology. Brain Behav. Immun. 69, 336–350 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reducing microglial progranulin expression in Aβ-mice impairs phagocytosis, raises plaque load, and worsens cognitive deficits.

    “Selective reduction of microglial expression of progranulin in Aβ-mice also impairs phagocytosis, increases plaque load, and exacerbates cognitive deficits.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Minami, S. S. et al. Progranulin protects against amyloid β deposition and toxicity in Alzheimer’s disease mouse models. Nat. Med. 20, 1157–1164 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because SRs bind diverse ligands, they are key sensors for misfolded proteins such as Aβ, mSOD1, aggregated α-synuclein, and PrPsc, possibly for clearance.

    “Because of their ability to bind a diverse class of ligands, SRs are important sensors of misfolded proteins including Aβ, mSOD1, aggregated α-synuclein, and PrPsc, possibly to clear them.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Multiple sclerosis patients have demyelinated plaques in white and gray matter; ongoing disease leads to progressive neurodegeneration and brain atrophy.

    “Multiple sclerosis (MS) patients have demyelinated plaques in the white and gray matter. Ongoing disease leads to progressive neurodegeneration, resulting in brain atrophy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Aβ binding to microglial RAGE (SR-J1) activates MAPK and NF-κB and, in 2- to 3-month-old animals, contributes to synaptic dysfunction via IL-1β release.

    “Binding of Aβ to the microglial SR-J1 (also called RAGE) activates MAPK and NF-κB and contributes to synaptic dysfunction through IL-1β release in 2- to 3-month-old animals139.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Origlia, N. et al. Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex. J. Neurosci. 30, 11414–11425 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Some SRs, like CD36, form complexes with other PRRs such as TLRs and trigger an inflammatory response leading to neurotoxicity and neurodegeneration.

    “Some of these receptors, such as CD36, form receptor complexes with other PRRS such as TLRs and initiate an inflammatory response that leads to neurotoxicity and neurodegeneration.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Huntington's disease is characterized by progressive atrophy of the striatum and cortex in advanced disease.

    “Huntington’s disease (HD) is characterized by progressive atrophy of the striatum and cortex in advanced disease69.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Ghosh, R. & Tabrizi, S. J. Huntington disease. Handb. Clin. Neurol. 147, 255–278 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    PET studies show widespread proinflammatory microglia in PD, but this response does not correlate with clinical severity, suggesting it occurs early.

    “Positron-emission tomography (PET) studies show widespread proinflammatory microglia, but this response does not correlate with clinical severity, suggesting it occurs early in the disease61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] 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.

  • May combine two claims.

    Premisecitation

    Progranulin deficiency causes age-dependent, progressive upregulation of lysosomal and innate immunity genes, more complement production, and enhanced C1q-dependent synaptic pruning by microglia.

    “Progranulin deficiency leads to age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced C1q-dependent synaptic pruning by microglia”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] 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.

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

    Interpretationreasoning

    AD and PD may share similar pathogenic pathways, raising the possibility that microglia are also a double-edged sword in PD.

    “These findings, which need to be validated in animal models of PD, suggest that AD and PD have similar pathogenic pathways, raising the possibility that microglia may also be a double-edged sword in PD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    In tauopathies, microglia first sense and clear tau, but dysregulation of Cx3cr1 and Trem2 pathways leads to dysregulated host defense and neuroinflammatory damage.

    “Microglia first sense and clear tau in an attempt to protect from tau toxicity, but dysregulation of microglial sensing and housekeeping pathways, such as the Cx3cr1 and Trem2 pathways, lead to dysregulation of the host-defense pathway, resulting in a neuroinflammatory response gone awry, causing neuronal damage and loss55–57.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [55] 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.

    • cites [56] Nash, K. R. et al. Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol. Aging 34, 1540–1548 (2013). source

      Not checked in the free run.

    • cites [57] Bemiller, S. M. et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12, 74 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuroinflammation is present in all stages of MS, and a proposed classification of MS lesions relies in part on the presence or absence of microglia.

    “Neuroinflammation is present in all stages of MS, and a proposed classification of MS lesions relies in part on the presence or absence of microglia in the lesions66.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Kuhlmann, T. et al. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 133, 13–24 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Scavenger receptors have complementary functions in microglia-Aβ interactions, with possible therapeutic relevance for AD.

    “These reports indicate that various SRs play complementary roles in microglia–Aβ interactions that may have therapeutic implications for AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the MPTP mouse model of PD, raising progranulin expression in nigrostriatal neurons accompanied reductions in MPTP-induced inflammation and apoptosis markers, protected these neurons from MPTP toxicity, and preserved striatal dopamine content and turnover.

    “In the MPTP mouse model of PD, upregulation of progranulin expression in nigrostriatal neurons was accompanied by reductions in markers of MPTP-induced inflammation and apoptosis, and it protected these neurons from MPTP toxicity and preserved striatal dopamine content and turnover.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Van Kampen, J. M., Baranowski, D. & Kay, D. G. Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson’s disease. PLoS One 9, e97032 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Progranulin is a secreted glycoprotein with neuro-immunomodulatory and autocrine neurotrophic roles important for long-term neuronal survival.

    “Progranulin is a secreted glycoprotein with neuro-immunomodulatory properties and autocrine neurotrophic functions important for long-term neuronal survival141.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Chitramuthu, B. P., Bennett, H. P. J. & Bateman, A. Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease. Brain 140, 3081–3104 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At six months, RAGE−/− Aβ-mice show less Aβ deposition and more Aβ-degrading enzymes.

    “Six-monthold RAGE−/− Aβ-mice have reduced Aβ deposition and more Aβ-degrading enzymes140.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Vodopivec, I. et al. RAGE does not affect amyloid pathology in transgenic ArcAbeta mice. Neurodegener. Dis. 6, 270–280 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Microglia internalize and degrade α-synuclein, possibly to clear it; a defect in this process leads to extracellular α-synuclein accumulation similar to Aβ.

    “Microglia internalize and degrade α-synuclein, possibly to clear it. A defect in this process leads to accumulation of extracellular α-synuclein similar to Aβ62.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Halliday, G. M. & Stevens, C. H. Glia: initiators and progressors of pathology in Parkinson’s disease. Mov. Disord. 26, 6–17 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD36 (SR-B2) is a microglial Aβ receptor; it complexes with TLR-4 and TLR-6, causing cytokine, chemokine, and ROS production, microglial migration, inflammasome activation, and neurotoxicity.

    “SR-B2 (also called CD36) is also a microglial Aβ receptor that forms a complex with TLR-4 and TLR-6, leading to cytokine, chemokine, and ROS production, as well as microglial migration, inflammasome activation, and neurotoxicity27,40.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] El Khoury, J. B. et al. CD36 mediates the innate host response to beta-amyloid. J. Exp. Med. 197, 1657–1666 (2003). source

      Not checked in the free run.

    • cites [40] Coraci, I. S. et al. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am. J. Pathol. 160, 101–112 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of the very-long-chain fatty-acid transporter ABCD1 increased complement activation and synapse loss and worsened microglial phagocytosis of neurons.

    “Deficiency in the very-long-chain fatty-acid transporter ABCD1 increased complement activation and synapse loss and aggravated microglial phagocytosis of neurons”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Gong, Y. et al. Microglial dysfunction as a key pathological change in adrenomyeloneuropathy. Ann. Neurol. 82, 813–827 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Five progranulin mutations (four missense and one 5′ regulatory variant) are linked to earlier ALS onset and shorter survival after onset.

    “Five progranulin mutations (four missense and one 5′ regulatory variant) are associated with reduction in age at onset and shorter survival after onset of ALS”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Sleegers, K. et al. Progranulin genetic variability contributes to amyotrophic lateral sclerosis. Neurology 71, 253–259 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Aβ-mice, altering gut microbiota affects Aβ deposition and changes microglial reactivity and morphology through unknown mechanisms.

    “In Aβ-mice, manipulating gut microbiota influences Aβ deposition and alters microglial reactivity and morphology by unknown mechanisms149.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Minter, M. R. et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci. Rep. 6, 30028 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Eliminating gut microbiota changes microglial numbers, size, transcriptomes, and surveillance functions and lowers host-defense genes.

    “Eradication of gut microbiota also alters microglial numbers, size, transcriptomes, and surveillance functions and downregulates host-defense genes147.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a PD model, antibiotics improve PD pathology, while oral specific microbial metabolites increase neuroinflammation and motor symptoms.

    “In a PD model, antibiotic treatment ameliorates PD pathology, whereas oral administration of specific microbial metabolites promotes neuroinflammation and motor symptoms150.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480.e12 (2016). source

      Not checked in the free run.

63 of 63

  • The paper relies on this without support.

    An accepted sequence in AD is that Aβ accumulation triggers a microglial response that promotes tau hyperphosphorylation and tangles, leading to neurodegeneration and cognitive impairment.

    “An accepted sequence of events is that accumulation of Aβ leads to a microglial response, which promotes tau hyperphosphorylation and formation of neurofibrillary tangles, leading to neurodegeneration and cognitive impairment.”

  • The paper relies on this without support.

    Cx3cr1 is expressed on perivascular macrophages.

    “However, as Cx3cr1 is also expressed on perivascular macrophages, studies using Cx3cr1−/− mice should be cautiously interpreted; the effects observed may also be attributed to perivascular macrophages.”

  • The paper relies on this without support.

    Microglia are the main neuroimmune cells of the CNS.

    “Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection.”

  • The paper relies on this without support.

    As disease progresses, SR expression falls, causing defective clearance and subsequent buildup of misfolded proteins.

    “With disease progression, SR expression decreases, leading to defective clearing and subsequent accumulation of these misfolded proteins.”
4 of 4

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?

  • Activated microglia can secrete pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, IL-18) or anti-inflammatory cytokines (e.g., IL-4, IL-10, TGF-β) depending on the dose, frequency, and context of stimulation.

    “Activated microglia can either secrete pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-18 or anti-inflammatory cytokines such as IL-4, IL-10, and transforming growth factor (TGF)-β depending on the dose, frequency, and context of the stimulation.4–7”

    From Tubular human brain organoids to model microglia-mediated neuroinflammation (2021) · cites this paper as [6]

    The “Protection against injurious self and non-self stimuli” section says that stimulated microglia produce cytokines including TNF and IL-1; the “Huntington’s disease” section also reports increased IL6 and TNF expression. Our copy does not substantiate the listed anti-inflammatory cytokines or the claim that cytokine secretion depends on stimulation dose and frequency. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Upon stimulation by factors such as TLR ligands, Aβ aggregates, complement factors, or opioids, microglia can shift from a homeostatic state to an activated state.

    “Upon stimulation by factors such as toll-like receptor (TLR) ligands, β-amyloid (Aβ) aggregates, complement factors, or opioids, microglia can shift from homeostatic state to an activated state.”

    From Tubular human brain organoids to model microglia-mediated neuroinflammation (2021) · cites this paper as [6]

    The sections “Protection against injurious self and non-self stimuli” and “Aβ-induced inflammation” (pages unavailable) describe microglial inflammatory responses to Aβ and interactions involving TLRs. They do not identify opioids or complement factors as stimuli that shift microglia into an activated state; the latter section mentions a complement receptor, which is not the same claim. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Complete deletion of CX3CR1 is associated with worsening memory deficits and tau pathology.

    “However, such complete deletion has also been associated with worsening memory deficits and tau pathology (28–31).”

    From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [31]

    The Cx3cr1–fractalkine > AD section says Cx3cr1 deficiency worsens tau pathology in mouse models. It does not report worsening memory deficits from complete CX3CR1 deletion, so that part of the claim is unsupported by our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Microglia are critically involved in ensuring the proper containment and removal of neurotoxic material in neurodegenerative disease pathogenesis.

    “Mounting evidence suggests that microglia, which are the professional phagocytes of the CNS, are critically involved in ensuring the proper containment and removal of neurotoxic material in neurodegenerative disease pathogenesis (Condello et al., 2015; Hickman et al., 2018; Lampron et al., 2015).”

    From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Hickman et al., 2018

  • Many studies suggest that microglia accumulate around Aβ plaques and clear Aβ deposits in transgenic mouse models of AD.

    “Although the role of microglia in AD is still debated, many studies suggest that microglia accumulate around Aβ plaques and clear Aβ deposits in transgenic mouse models of AD (27, 28).”

    From Deletion of <i>Abi3</i> gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [28]

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.

  • RAGE result conflicts with the cited reference title

    Minor

    The text says RAGE deletion reduced Aβ deposition in six-month-old mice, but the title of the cited study says RAGE does not affect amyloid pathology in those mice. The age-specific result and the reference title therefore give conflicting accounts of the effect.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Río Hortega, P. Noticia de un nuevo y fácil método para la coloración de la neuroglia y el tejido conjuntivo. Trab. Lab. Invest. Biol. 15, 367–378 (1918).
  2. El Khoury, J. & Hickman, S.E. Mechanisms of amyloid-beta clearance in Alzheimer’s disease. in Research Progress in Alzheimer’s Disease and Dementia, vol. 4. (ed. Sun, M.-K.) 37–66 (Nova Science Publishers, Hauppauge, NY, USA, 2009).

Cited by

Sorted by citations

Related

Authors
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J.
Affiliations
Harvard University (US)
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2018-09-26
Volume
21
Issue
10
Pages
1359-1369
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-018-0242-x
PMC
PMC6817969
OpenAlex
W2890627020
Semantic Scholar
6c3dc4c2185e67c22814f92d9ba41db084d006b4
Cited by
1,710
References
149
Citations by year
2026: 154 · 2025: 225 · 2024: 307 · 2023: 274 · 2022: 267 · 2021: 217 · 2020: 174 · 2019: 87 · 2018: 5
FWCI
11.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (RF1AG051506)
  • National Institute of Allergy and Infectious Diseases (T32AI007061)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
microglia, neurodegeneration, neuroinflammation, neuroimmune system, neuroprotection, TREM2, CX3CR1, progranulin, scavenger receptors, peripheral inflammation, gut microbiota, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, amyotrophic lateral sclerosis, frontotemporal dementia, chronic traumatic encephalopathy
MeSH terms
Animals, Humans, Inflammation, Microglia, Neurodegenerative Diseases

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.

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