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Cited by 278Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsNeuroscience and Neuropharmacology Research

Beyond Activation: Characterizing Microglial Functional Phenotypes

Open access
Lier, Julia, Streit, Wolfgang J., Bechmann, Ingo·2021·Cells
DOI 10.3390/cells10092236PMC PMC8464670
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Abstract

Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an “expiration date” limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that microglial functional phenotypes cannot be reliably inferred from single morphological or antigenic markers, because markers such as IBA1, TMEM119, P2RY12, CD74, MHCII, and CD68 vary across states and diseases. It highlights IBA1-low/negative microglia, including in individuals with liver disease, and calls for combining morphology, marker panels, and transcriptomic signatures.

Key findings

  • Four morphological microglial phenotypes are distinguished—resting, activated, amoeboid, and dystrophic—but IBA1 reliably stains ramified, activated, amoeboid, and dystrophic microglia, so it cannot distinguish functional phenotypes.
  • IBA1 loss or decrease is reported in human hippocampus with hepatic pathologies, non-proliferative hepatic encephalopathy, schizophrenia temporal cortex, Huntington’s disease striatum, and Alzheimer’s disease cortex; IBA1-low Alzheimer’s populations showed increased ferritin, CD74, and CD45, while plaque-associated microglia expressed high HLA-DR but much less IBA1.
  • TMEM119 was expressed in at least 50% of IBA1-positive human microglia and in 98% of rodent CD45lowCD11b+ cells, but was absent in necrotic cerebral infarctions and demyelinating multiple sclerosis lesions; in Alzheimer’s disease, TMEM119 mRNA was elevated although immunohistochemical analyses showed no difference.
  • P2RY12 is specific for parenchymal microglia and downregulated during activation/disease-associated states; CD74 was expressed in all human microglial morphological states; CD68 is a lysosomal/phagocytic marker, and a cluster from 16,096 individual microglial transcriptomes with distinct CD68 upregulation was most enriched for disease-associated microglia genes.

Methods

  • Narrative review; the authors review commonly used microglial markers and their expression fluctuations in health and disease, with a focus on IBA1-low/negative microglia found in individuals with liver disease.
  • Evidence base consists of cited human and rodent studies using immunohistochemistry, single-cell RNA sequencing, and disease models including Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, schizophrenia, and hepatic encephalopathy.
  • Main analysis is a qualitative synthesis of marker expression across morphological states and pathologies; no systematic search strategy or meta-analysis is described.

Limitations

  • Stated: associating single markers with a distinct phenotype is difficult because most markers are expressed in several or even all microglial functional states.
  • Stated: many studies use IBA1 as the sole microglial marker, so they have not discriminated between a reduction in total microglial numbers and decreased IBA1 expression; the exact function of IBA1 still needs to be elucidated, and species differences are noted, such as CD74 expression in human versus rodent microglia.
  • Evident from the text: as a narrative review, it lacks a systematic search, explicit inclusion criteria, and quantitative synthesis, so its conclusions depend on the cited literature and may be subject to selection or reporting bias.

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

Integrity signals

Registry

Crossref · 10.3390/cells10092236

Cites

110 of 110 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

44 of 63 cited sources checked · 22 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    IBA1 cannot be used to distinguish between functional microglial phenotypes.

    “Even though IBA1 is often characterized as a typical microglial activation marker [8,9,10], it cannot be used to distinguish between functional microglial phenotypes [2].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] Walker, 2015, Immune phenotypes of microglia in human neurodegenerative disease: Challenges to detecting mi-croglial polarization in human brains, Alzheimers Res. Ther. source
  • Premisecitation

    Following transient middle cerebral artery occlusion in rats, IBA1 staining density and intensity were strongly increased in the ischemic core and ischemic border zone compared to the non-affected hemisphere.

    “Following the transient occlusion of the middle cerebral artery (MCA) in rats, the IBA1 staining density and intensity were strongly increased in the ischemic core and the ischemic border zone, compared to the non-affected hemisphere [13].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Michalski, 2017, Delayed histochemical alterations within the neurovascular unit due to transient focal cerebral ischemia and experimental treatment with neurotrophic factors, PLoS ONE source
  • Interpretationcitation

    Associating single markers to a distinct microglial phenotype is difficult, since most markers are expressed in several or even all microglial functional states.

    “However, as we will describe in this review, associating single markers to a distinct phenotype is difficult, since most markers are expressed in several or even all microglial functional states (Figure 1, [2]).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [2] Walker, 2015, Immune phenotypes of microglia in human neurodegenerative disease: Challenges to detecting mi-croglial polarization in human brains, Alzheimers Res. Ther. source

      The Abstract says that widely used microglial markers do not distinguish different phenotypes, and the CD68 section says that both M1- and M2-polarized cells can express CD68. These passages support the difficulty of assigning a phenotype from a single marker, but do not establish that most markers are expressed in several or all functional states. Page numbers are unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Expression of AIF-1, the gene for IBA1, on microglia does not differ between white matter and grey matter.

    “While the distribution of microglia varies between different brain regions [11], the expression of allograft inflammatory factor 1 (AIF-1, gene for IBA1) on microglia does not differ between white matter and grey matter [12].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Vlaar, 2019, Regulation of microglial TMEM119 and P2RY12 immunoreactivity in multiple sclerosis white and grey matter lesions is dependent on their inflammatory envi-ronment, Acta Neuropathol. Commun. source
  • Premisecitation

    IBA1 is also expressed by peripheral macrophages, unlike homeostatic microglial markers such as TMEM119 or P2RY12.

    “In contrast to so-called homeostatic microglial markers, such as transmembrane protein (TMEM-)119 or P2RY12, IBA1 is also expressed by peripheral macrophages [4,5,6,7].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [4] Buckman, 2014, Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system, Brain Behav. Immun. source

      Results §3.4 reports that most recruited, donor-derived GFP+ cells in the brain expressed Iba1, supporting the point that IBA1 is not restricted to resident microglia. The paper does not address TMEM119 or P2RY12 or compare their expression with IBA1, so it does not support that part of the sentence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [5] 2007, Allograft inflammatory factor-1/Ionized calcium-binding adapter molecule 1 is specifically expressed by most subpopulations of macrophages and spermatids in testis, Cell Tissue Res. source
    • cites [6] Leone, 2006, Characterization of human monocyte-derived mi-croglia-like cells, Glia source
    • cites [7] Sasaki, 2001, Iba1 Is an Actin-Cross-Linking Protein in Macrophages/Microglia, Biochem. Biophys. Res. Commun. source
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    Compared with homeostatic microglia, disease-associated microglia are characterized by downregulation of AIF1 and homeostatic genes such as P2RY12, TMEM119, and Cx3Cr1, while CD74 and CD68 are upregulated.

    “Compared with homeostatic microglia, DAM were characterized by the downregulation of AIF1 and homeostatic genes, such as P2RY12, TMEM119, Cx3Cr1, while CD74 and CD68 were upregulated (Supplementary Material in [28]).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [28] Spinrad, 2017, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease, Cell source

      The Results (page unavailable; Figures 1B, 1E, and S1D) report lower P2ry12, Cx3cr1, and Tmem119 expression in DAM than in homeostatic microglia. The passages found do not establish downregulation of AIF1 or upregulation of CD74 and CD68; the paper instead names other upregulated DAM genes, including Apoe, Lpl, and Cst7. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TREM2 deficiency results in lower transcription levels of IBA1 and a decrease in IBA1-positive microglia, visible at every timepoint tested and increasing with age.

    “Consistent with these results, experiments investigating the deficiency of TREM2 detected lower transcription levels of IBA1 and a decrease in IBA1-positive microglia. This observation was visible at every timepoint tested and even increased with age [35].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Bodea, 2019, TREM2 triggers microglial density and age-related neuronal loss, Glia source

  • May combine two claims.

    Premisecitation

    Single-cell deep sequencing methods revealed regional-, age- and sex-dependent differences of the microglial population and various expression profiles defining microglial subpopulations.

    “Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations.”
    Quote in the paperSubstantial claim5 of 6 sources checked
    • cites [28] Spinrad, 2017, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease, Cell source

      The Results report that single-cell RNA-seq identified distinct microglial expression profiles, including disease-associated microglia, and found changes across disease stages and between young and aged mice. They also locate these cells near amyloid plaques, but do not establish broad differences between brain regions. The paper uses sex-matched controls; the passages do not report sex-dependent differences. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [39] Olah, 2020, Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease, Nat. Commun. source

      The Introduction and Results report that single-cell RNA sequencing identified nine human microglial subpopulations with distinct expression profiles. However, the Results say the observed differences between sample sets could not be resolved as effects of age, brain region, sample type, or diagnosis; the cited passages do not establish sex-dependent differences either. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [99] Ayata, 2018, Epigenetic regulation of brain region-specific microglia clearance activity, Nat. Neurosci. source

      The Discussion (page unavailable) reports distinct striatal and cerebellar microglial expression profiles and says single-nucleus RNA sequencing helped assess microglial diversity. The Single nuclei sequencing Methods (page unavailable) specify 4-month-old female mice; although the bulk-sequencing Methods list other ages and sexes, the cited paper does not establish age- or sex-dependent differences through its single-nucleus analysis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [102] Hammond, 2019, Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes, Immunity source

      The Results sections on developmental subpopulations and axon tract–associated microglia report age-dependent transcriptional states and a subpopulation localized to particular brain regions. But the Results section on sex says clustering differed almost not at all between males and females, with only one very small female-enriched cluster; it concludes that diversity was largely unaffected by sex. Thus the sex-dependent part overstates this paper's findings. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [108] Li, 2019, Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing, Neuron source

      The Results describe developmental changes in microglial gene expression and distinct microglial clusters; the Discussion reports discovery of the PAM subset. But the Results and Discussion find little transcriptomic variation among classical adult microglia across the regions tested, and STAR Methods state that only male mice were used. This paper therefore does not establish the claimed sex-dependent differences, and its regional finding is more qualified than the claim suggests. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [109] Patir, 2019, A core transcriptional signature of human microglia: Derivation and utility in describing region-dependent alterations associated with Alzheimer’s disease, Glia source

  • May combine two claims.

    Premisecitation

    IRF8-deficient microglia show significantly reduced levels of IBA1 but no deficits in phagocytosis.

    “However, experiments using interferon regulatory factor 8 (IRF8)-deficient microglia [36], showed significantly reduced levels of IBA1, but no deficits in phagocytosis.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Minten, C., Terry, R., Deffrasnes, C., King, N.J.C., and Campbell, I.L. (2012). IFN Regulatory Factor 8 Is a Key Constitutive Determinant of the Morphological and Molecular Properties of Microglia in the CNS. PLoS ONE, 7. source

  • May combine two claims.

    Premisecitation

    CD68 is mainly expressed in the soma of ramified microglia, so typical extrusions cannot be observed with CD68 staining, making it a non-suitable marker for examining microglial morphology.

    “As a lysosomal marker, CD68 is mainly expressed in the soma of ramified microglia. Therefore, the typical extrusions cannot not be observed with CD68 staining ([27], Figure 1), making it a non-suitable marker in the examination of microglial morphology.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] Hendrickx, 2017, Staining of HLA-DR, Iba1 and CD68 in human microglia reveals partially overlapping expression depending on cellular morphology and pathology, J. Neuroimmunol. source

  • May combine two claims.

    Premisecitation

    Subsequent downregulation of P2RY12 induces retraction of microglial processes and leads to morphological activation.

    “However, subsequent downregulation of P2RY12 induces the retraction of microglial processes and therefore leads to morphological activation [57].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] Koizumi, 2013, Purinergic receptors in microglia: Functional modal shifts of microglia mediated by P2 and P1 receptors, Glia source

      The PROCESS-RETRACTING MICROGLIA section (page not provided) reports that LPS activation decreases P2Y12 expression and that a change in the balance of P2Y12 and A2A receptors may partly explain a shift toward amoeboid morphology. It attributes process retraction to adenosine signaling through A2A, not to P2Y12 downregulation alone. The claim therefore overstates a causal role for P2Y12 downregulation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    CD74 is necessary for blocking the peptide-binding site of MHCII molecules during their transport from the endoplasmic reticulum to the cell surface.

    “CD74 is also known as the invariant chain and it is necessary for blocking the peptide-binding site of MHCII molecules during their transport from the endoplasmatic reticulum to the cell surface [66,67,68].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [66] Radomir, 2017, CD74 is a novel transcription regulator, Proc. Natl. Acad. Sci. USA source

      The opening section (page unavailable) says CD74 functions as an MHC class II chaperone, and the References identify invariant chain with CD74. Our copy does not say that CD74 blocks the MHCII peptide-binding site or specify that it does so during transport from the endoplasmic reticulum to the cell surface. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [67] 2016, The multifaceted roles of the invariant chain CD74—More than just a chaperone, Biochim. Biophys. Acta Bioenerg. source
    • cites [68] Arie, 2005, CD74 Is a Member of the Regulated Intramembrane Pro-teolysis-processed Protein Family, Mol. Biol. Cell source

  • May combine two claims.

    Premisecitation

    MHCII expression precedes and regulates dopaminergic neurodegeneration in the substantia nigra.

    “Furthermore, MHCII expression precedes and regulates dopaminergic neurodegeneration in the substantia nigra [94,95,96].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [94] Jewett, 2021, The MHC class II transactivator modulates seeded alpha-synuclein pathology and dopaminergic neurodegeneration in an in vivo rat model of Parkinson’s disease, Brain Behav. Immun. source
    • cites [95] Subbarayan, 2020, T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s disease, J. Neuroinflamm. source

      The Results section (Fig. 6; page not provided) says microglial MHCII expression increased alongside dopamine-neuron loss in the substantia nigra, not that it preceded the loss. The Discussion says the findings suggest that T-cell interaction with microglia involving MHCII upregulation is necessary for neuronal loss in this α-synuclein rat model, supporting a qualified regulatory role. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [96] Harms, 2013, MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration, J. Neurosci. source

  • May combine two claims.

    Premisecitation

    In an analysis of 16,096 individual microglial transcriptomes, the cluster with distinct CD68 upregulation was most enriched for DAM genes such as CD74, HL-DRB1 and ITM2B and was associated with inflammatory demyelination, ischemia and Alzheimer's disease.

    “In an analysis of 16,096 individual microglial transcriptomes, the cluster depicting a distinct upregulation of CD68 was most enriched for DAM genes, such as CD74, HL-DRB1 and ITM2B and was associated with pathologic conditions, such as inflammatory demyelination, ischemia and AD [39].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Olah, 2020, Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease, Nat. Commun. source

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

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    The mere homeostatic function of P2RY12 needs to be challenged because P2RY12-positive microglia also expressed activation markers such as CD68, progranulin and, to a limited extent, HLA-DR.

    “Since, in this study, microglia that were positive for P2RY12 also expressed markers of activation, such as CD68, progranulin and to a limited extent, HLA-DR, the mere homeostatic function of P2RY12 needs to be challenged.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [64] Walker, D.G., Tang, T.M., Mendsaikhan, A., Tooyama, I., Serrano, G.E., Sue, L.I., Beach, T.G., and Lue, L.-F. (2020). Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer’s Disease Brains. Int. J. Mol. Sci., 21. source

  • May combine two claims.

    Premisecitation

    CD68 is indicative of phagocytic activity and is upregulated in cell culture after treatment with pro-inflammatory cytokines, lipopolysaccharide and IFNγ.

    “It is indicative of phagocytic activity [2], and is upregulated in cell culture experiments after treatment with pro-inflammatory cytokines, lipopolysaccharide (LPS) and IFNγ [98].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [2] Walker, 2015, Immune phenotypes of microglia in human neurodegenerative disease: Challenges to detecting mi-croglial polarization in human brains, Alzheimers Res. Ther. source
    • cites [98] Wong, 2005, Macrosialin increases during normal brain aging are attenuated by caloric restriction, Neurosci. Lett. source

  • May combine two claims.

    Premisecitation

    TMEM119 is stably and specifically expressed in microglia and can be used to distinguish microglia from resident and infiltrating macrophages.

    “TMEM119 has been shown to be stably and specifically expressed in microglia [41,44], and it can be used to distinguish microglia from resident and infiltrating macrophages [41].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [41] Bennett, 2016, New tools for studying microglia in the mouse and human CNS, Proc. Natl. Acad. Sci. USA source
    • cites [44] Bonham, 2019, The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease, Front. Immunol. source

      The Introduction describes TMEM119 as a specific microglial marker that distinguishes microglia from other myeloid cells, including perivascular and infiltrating macrophages. The Methods also calls it a highly specific, well-validated marker. Neither passage establishes that its expression is stable, so that part of the claim is unsupported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Our group identified areas in the human hippocampus where a localized loss of IBA1 expression was observed, whereas other microglial markers such as GPX1 or P2RY12 were still present.

    “Formerly thought to be expressed by all microglial subpopulations [2], our group identified areas in the human hippocampus where a localized loss of IBA1 expression was observed [21], whereas other microglial markers, such as GPX1 or P2RY12, were still present.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Lier, 2019, Loss of IBA1-Expression in brains from individuals with obesity and hepatic dysfunction, Brain Res. source

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

    Premisenone given

    Morphologically, four microglial phenotypes can be distinguished: resting, activated, amoeboid, and dystrophic microglia.

    “Morphologically, the following four microglial phenotypes can be distinguished: resting, activated, amoeboid, and dystrophic microglia (Table 1, Figure 1).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    IBA1 has been the most widely used marker for the immunohistochemical analysis of microglia since its first description in 1998.

    “Since its first description in 1998 [3], IBA1 has been the most widely used marker for the immunohistochemical analysis of microglia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Ito, 1998, Microglia-specific localisation of a novel calcium binding protein, Iba1, Mol. Brain Res. source

  • May combine two claims.

    Premisecitation

    CD74 expression occurs independently from concomitant MHCII expression and is also expressed on non-antigen-presenting cells.

    “However, it was shown that CD74 expression occurred independently from concomitant MHCII expression, and it is also expressed on non-antigen-presenting cells [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Henne, 1995, Surface expression of the invariant chain (CD74) is independent of concomitant expression of major histocompatibility complex class II antigens, Immunology

  • May combine two claims.

    Premisecitation

    P2RY12 is specific for parenchymal microglia and shows persistent expression during the lifespan of microglia.

    “The G-protein-coupled purinergic receptor P2RY12 [51] is specific for parenchymal microglia [52] and shows a persistent expression during the lifespan of microglia [53].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] 2021, Shaping Neuronal Fate: Functional Heterogeneity of Direct Microglia-Neuron Interactions, Neuron source
    • cites [53] Mildner, 2017, P2Y12receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases, Glia source

  • May combine two claims.

    Premisecitation

    Necrotic lesions of cerebral infarctions and demyelinating lesions of multiple sclerosis were devoid of TMEM119 expression.

    “However, necrotic lesions of cerebral infarctions and demyelinating lesions of multiple sclerosis were devoid of TMEM119 expression [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Satoh, 2016, TMEM119 marks a subset of microglia in the human brain, Neuropathology source
18 of 18

  • The paper relies on this without support.

    Microglia are not replenished by blood-borne mononuclear cells under physiological circumstances.

    “Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances”

  • The authors state this as an assumption.

    Certain microglial dysfunctions associated with a loss of IBA1 may not be pathology specific, but have a broader impact on immune defense and synaptic plasticity.

    “it is reasonable to assume that certain microglial dysfunctions that are associated with a loss of IBA1 may not be pathology specific, but have a broader impact on their role in immune defense and synaptic plasticity.”
2 of 2

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Each contradiction between two passages listed here was confirmed by an independent check.

  • Huntington's disease claim cites an Alzheimer's disease paper

    Minor

    The text attributes a finding about Huntington's disease to Bulk et al. [25], but the listed title of reference 25 identifies its subject as early- and late-onset Alzheimer's disease.

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Related

Authors
Lier, J., Streit, W. J., & Bechmann, I.
Affiliations
  • Leipzig University (DE)
  • University of Florida Health (US)
Corresponding author
Lier, Julia
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2021-08-28
Volume
10
Issue
9
Pages
2236
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells10092236
PMC
PMC8464670
OpenAlex
W3196760175
Cited by
274
References
112
Citations by year
2026: 50 · 2025: 74 · 2024: 90 · 2023: 40 · 2022: 20
FWCI
12.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, other-oa)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Qucosa (Saxon State and University Library Dresden) (submittedVersion, cc-by)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
microglia, microglial activation, microglial morphology, ramified microglia, amoeboid microglia, microglial senescence, microglial heterogeneity, microglial markers, Iba1, liver disease, Alzheimer's disease, neurodegeneration, brain aging
MeSH terms
CD68 Molecule, Animals, Antigens, Differentiation, B-Lymphocyte, Histocompatibility Antigens Class II, Brain, Calcium-Binding Proteins, Humans, Membrane Proteins, Microfilament Proteins, Nerve Tissue Proteins, Phagocytes, Phenotype, Antigens, Differentiation, Myelomonocytic, Signal Transduction, Antigens, CD, Microglia, Neurodegenerative Diseases, Receptors, Purinergic P2Y12

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