The DOI matches its Crossref record; 110 of the 112 references it cites were found in a registry or an index; 44 of the 63 sources its claims cite were checked for support.
Beyond Activation: Characterizing Microglial Functional Phenotypes
Open accessAbstract
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.
Overview
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.
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Claims the paper makes
15 Supported · 13 Partly supported · 8 No full text of the sources · 4 Own interpretation · 2 Supported so far · 2 Own result · 2 No basis given · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Supportedcites [2] Walker, 2015, Immune phenotypes of microglia in human neurodegenerative disease: Challenges to detecting mi-croglial polarization in human brains, Alzheimers Res. Ther. source
In “Microglia in human brains,” the paper says IBA-1 identifies all microglia and is not useful for identifying their immune phenotype or polarity. This directly supports the attributed claim. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Supportedcites [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
The Results section, “Vascular and glial alterations in relation to the ischemic lesion in untreated animals,” reports that Iba staining density and intensity were highest in the ischemic core, lower in the border zone, and lower still in the contralateral striatum, with significant differences between regions. This supports increased staining in both ischemic regions relative to the non-affected hemisphere. (LLM, conf=0.91)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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]).”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 1. Introduction
What the sources say
- Partly supportedcites [2] Walker, 2015, Immune phenotypes of microglia in human neurodegenerative disease: Challenges to detecting mi-croglial polarization in human brains, Alzheimers Res. Ther. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Supportedcites [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
The Results section on primary human microglia states that AIF-1 expression did not differ between microglia derived from white matter and grey matter. This directly supports the attributed comparison; the measurements were made in cultured, tissue-derived microglia. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [6] Leone, 2006, Characterization of human monocyte-derived mi-croglia-like cells, Glia source
- Not checked — no full text of the sourcecites [7] Sasaki, 2001, Iba1 Is an Actin-Cross-Linking Protein in Macrophages/Microglia, Biochem. Biophys. Res. Commun. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In contrast, studying the long-term effects of a high-fat, high-carbohydrate diet (HFCD) in the hippocampus of rats, Gzielo et al. [19] showed that the area fraction covered by IBA1-positive cells was reduced after consumption for one year.”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Supportedcites [19] Gzielo, 2016, Long-Term Consumption of High-Fat Diet in Rats: Effects on Microglial and Astrocytic Morphology and Neuronal Nitric Oxide Synthase Expression, Cell. Mol. Neurobiol. source
The Introduction states that the rats received a high-fat, high-carbohydrate diet for 12 months. The Results (Area Fraction) report significantly lower hippocampal Iba1-immunoreactive area fraction in those rats than in controls. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“In fact, we have shown that dystrophic, much more than activated microglia are present in human AD [83,104,107].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 7. CD68
What the sources say
- Supportedcites [83] Streit, 2009, Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease, Acta Neuropathol. source
The Discussion reports dystrophic microglia accompanying neuritic plaques and says the authors did not observe activated microglia across cases ranging from no to severe AD pathology. This supports the citing sentence’s comparison in human AD. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [104] Streit, 2018, Microglial activation occurs late during preclinical Alzheimer’s disease, Glia source
- Not checked — no full text of the sourcecites [107] Streit, 2020, Dystrophic microglia in late-onset Alzheimer’s disease, Glia source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“CD74 was characterized as a cell surface receptor for the macrophage migration inhibitory factor (MIF, [70,71]).”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 5. CD74
What the sources say
- Supportedcites [70] Farr, 2020, Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair, Front. Immunol. source
The section “CD74 Is A Receptor for MIF Cytokine” states that CD74 was identified as the MIF receptor and that MIF binds its extracellular domain. The “CD74” section also describes CD74 expression on cell surfaces. Page numbers are not provided in the supplied copy. (LLM, conf=0.94)
- Supportedcites [71] Leng, 2003, MIF Signal Transduction Initiated by Binding to CD, J. Exp. Med. source
The Abstract identifies CD74 as a high-affinity binding protein for MIF and reports that MIF binds its extracellular domain. The Discussion describes CD74 as a membrane receptor for MIF and confirms that CD74 is expressed on the cell surface. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“and microglia upregulate HLA-DR in response to IFNγ stimulation [27].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 6. MHCII
What the sources say
- Supportedcites [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
The Introduction explicitly states that microglia upregulate HLA-DR in response to interferon (IFN)-γ stimulation. The claim accurately paraphrases that statement. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“while rodent studies even demonstrated an expression of 98% of CD45lowCD11b+ cells in adult animals [41].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 3. TMEM119
What the sources say
- Supportedcites [41] Bennett, 2016, New tools for studying microglia in the mouse and human CNS, Proc. Natl. Acad. Sci. USA source
In “Custom Anti-Tmem119 Monoclonal Antibodies Specifically Identify Microglia,” the authors report that 98.1 ± 0.6% of CD45loCD11b+ cells were Tmem119+ in adult (P60) mice. This supports the citing sentence’s rounded 98% figure for adult rodents. (LLM, conf=0.94)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- It may state two separate claims as one. 15
- Probably not a substantial claim. 3
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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]).”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Partly supportedcites [28] Spinrad, 2017, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease, Cell sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Supportedcites [35] Bodea, 2019, TREM2 triggers microglial density and age-related neuronal loss, Glia source
The Results section reports lower transcription of Aif1, the Iba1-encoding gene, in TREM2 knockout mice, especially at 24 months. It also reports fewer Iba1-positive cells at every investigated time point, with the difference especially pronounced at 24 months. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > Abstract
What the sources say
- Partly supportedcites [28] Spinrad, 2017, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease, Cell sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [39] Olah, 2020, Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease, Nat. Commun. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [99] Ayata, 2018, Epigenetic regulation of brain region-specific microglia clearance activity, Nat. Neurosci. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [102] Hammond, 2019, Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes, Immunity sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [108] Li, 2019, Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing, Neuron sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, experiments using interferon regulatory factor 8 (IRF8)-deficient microglia [36], showed significantly reduced levels of IBA1, but no deficits in phagocytosis.”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Supportedcites [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
The Results section on altered molecular properties reports significantly reduced Iba1 levels in IRF8-deficient microglia. The Results section on phagocytosis reports no significant difference from wild-type microglia in fluorescent E. coli particle uptake across the tested time points, supporting the stated absence of a detected phagocytosis deficit in that assay. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 7. CD68
What the sources say
- Supportedcites [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
The passage labeled “Nimmerjahn” says CD68 is primarily on lysosomal membranes, that lysosomes in ramified microglia are mainly near the nucleus, and that typical extrusions therefore cannot be observed with CD68 staining. The conclusion says CD68 is least useful for studying morphology because of its intracellular expression. Page numbers are not provided in our copy. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, subsequent downregulation of P2RY12 induces the retraction of microglial processes and therefore leads to morphological activation [57].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 4. P2RY12
What the sources say
- Partly supportedcites [57] Koizumi, 2013, Purinergic receptors in microglia: Functional modal shifts of microglia mediated by P2 and P1 receptors, Glia sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 5. CD74
What the sources say
- Partly supportedcites [66] Radomir, 2017, CD74 is a novel transcription regulator, Proc. Natl. Acad. Sci. USA sourceExperimental — accuracy not yet measured
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)
- Supportedcites [67] 2016, The multifaceted roles of the invariant chain CD74—More than just a chaperone, Biochim. Biophys. Acta Bioenerg. source
Section 3 states that CD74 blocks the MHCII antigen-binding site and prevents premature peptide binding during the biosynthetic pathway. Sections 3 and 3.1 describe its association with MHCII in the ER and its role in directing MHCII to antigen-processing compartments, supporting the transport context of the paraphrase. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [68] Arie, 2005, CD74 Is a Member of the Regulated Intramembrane Pro-teolysis-processed Protein Family, Mol. Biol. Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Furthermore, MHCII expression precedes and regulates dopaminergic neurodegeneration in the substantia nigra [94,95,96].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 6. MHCII
What the sources say
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [96] Harms, 2013, MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration, J. Neurosci. source
In the α-synuclein overexpression mouse model, the Results report increased microglial MHCII expression in the substantia nigra at 4 weeks and dopaminergic neuron loss at 6 months. The same section reports that MHCII knockout prevented that neuron loss, supporting a regulatory role in this model. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 7. CD68
What the sources say
- Partly supportedcites [39] Olah, 2020, Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease, Nat. Commun. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelationaln = 16,096- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 4. P2RY12
What the sources say
- Supportedcites [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
The Introduction reports CD68 and progranulin in most P2RY12-positive microglia and says that classifying P2RY12 expression as a marker of homeostatic microglia needs reconsideration. Results §2.6 reports limited colocalization with HLA-DR, matching the claim’s qualification. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 7. CD68
What the sources say
- Supportedcites [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 CD68 section states that CD68 is upregulated in actively phagocytic cells, supporting the clause attributed to this source [2]. The cell-culture treatment clause is separately attributed to [98] and is not part of this verdict. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [98] Wong, 2005, Macrosialin increases during normal brain aging are attenuated by caloric restriction, Neurosci. Lett. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 3. TMEM119
What the sources say
- Supportedcites [41] Bennett, 2016, New tools for studying microglia in the mouse and human CNS, Proc. Natl. Acad. Sci. USA source
The section “Tmem119 Is a Specific and Stable Marker of Microglia in Mouse and Human” describes it as highly specific and reports stable identification after injury and inflammation. “Macrophages After CNS Inflammation and Injury” reports that Tmem119 labeled resident microglia, not infiltrating macrophages; the mRNA-specificity section also reports its absence from meningeal, choroid plexus, and perivascular macrophages. (LLM, conf=0.94)
- Partly supportedcites [44] Bonham, 2019, The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease, Front. Immunol. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
In the paper
“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.”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Not checked — no full text of the sourcecites [21] Lier, 2019, Loss of IBA1-Expression in brains from individuals with obesity and hepatic dysfunction, Brain Res. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Morphologically, the following four microglial phenotypes can be distinguished: resting, activated, amoeboid, and dystrophic microglia (Table 1, Figure 1).”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 1. Introduction
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Since its first description in 1998 [3], IBA1 has been the most widely used marker for the immunohistochemical analysis of microglia.”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
What the sources say
- Not checked — no full text of the sourcecites [3] Ito, 1998, Microglia-specific localisation of a novel calcium binding protein, Iba1, Mol. Brain Res. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“However, it was shown that CD74 expression occurred independently from concomitant MHCII expression, and it is also expressed on non-antigen-presenting cells [69].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 5. CD74
What the sources say
- Not checked — no full text of the sourcecites [69] Henne, 1995, Surface expression of the invariant chain (CD74) is independent of concomitant expression of major histocompatibility complex class II antigens, Immunology
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 4. P2RY12
What the sources say
- Not checked — no full text of the sourcecites [52] 2021, Shaping Neuronal Fate: Functional Heterogeneity of Direct Microglia-Neuron Interactions, Neuron source
- Not checked — no full text of the sourcecites [53] Mildner, 2017, P2Y12receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases, Glia source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, necrotic lesions of cerebral infarctions and demyelinating lesions of multiple sclerosis were devoid of TMEM119 expression [45].”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 3. TMEM119
What the sources say
- Not checked — no full text of the sourcecites [45] Satoh, 2016, TMEM119 marks a subset of microglia in the human brain, Neuropathology source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“Moreover, decreased Iba1 expression and even Iba1- microglia have previously been described in neurodegenerative disorders such as Huntington’s and Alzheimer’s disease50.”
From CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis (2024) · cites this paper as [50]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > 2. IBA1
“In the striatum, Bulk et al. [25] demonstrated an association between an advanced disease state in patients suffering from Huntington’s disease and IBA1-negative microglia.”
§ Beyond Activation: Characterizing Microglial Functional Phenotypes > References
“Bulk M. Abdelmoula W.M. Nabuurs R.J.A. van der Graaf L.M. Mulders C.W.H. Mulder A.A. Postmortem MRI and histology demonstrate differential iron accumulation and cortical myelin organization in early- and late-onset Alzheimer’s disease”
Citations
Cites
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · cited 4×
“[28] demonstrated significant changes in the rodent gene expression of disease-associated microglia (DAM), a concept that was primarily described in a mouse model of Alzheimer’s disease [28].”
BackgroundInfluentialKrasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · cited 1×
“The triggering receptor expressed on myeloid cells (TREM)-2 serves as a binding partner for apolipoprotein E (APOE, [29]), and especially the ε4 allele has been shown to act as a risk factor for Alzheimer’s disease [30,31].”
BackgroundIdentification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543
Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Walker, A. J., Segel, M., Nemesh, J., Saunders, A., et al. (2018) · doi:10.1101/406140 · Cited by 2,225
Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain
Lawson, L. J., Perry, V. H., Dri, P., & Gordon, S. (1990) · Neuroscience · doi:10.1016/0306-4522(90)90229-w · Cited by 2,045 · cited 1×
“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].”
BackgroundObesity is associated with hypothalamic injury in rodents and humans.
Thaler, J. P., Yi, C.-X., Schur, E. A., Guyenet, S. J., Hwang, B. H., Dietrich, M. O., Zhao, X., Sarruf, D. A., Izgur, V., Maravilla, K. R., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59660 · Cited by 1,857
New tools for studying microglia in the mouse and human CNS
Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525528113 · Cited by 1,804 · cited 2×
“In human brains, at least 50% of the IBA1-positive microglial population were positive for TMEM119 [45], while rodent studies even demonstrated an expression of 98% of CD45lowCD11b+ cells in adult animals [41].”
BackgroundA polarizing question: do M1 and M2 microglia exist?
Ransohoff, R. M. (2016) · Nature Neuroscience · doi:10.1038/nn.4338 · Cited by 1,573
The P2Y12 receptor regulates microglial activation by extracellular nucleotides
Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W.-B., & Julius, D. (2006) · Nature Neuroscience · doi:10.1038/nn1805 · Cited by 1,542
The microglial sensome revealed by direct RNA sequencing
Hickman, S. E., Kingery, N. D., Ohsumi, T. K., Borowsky, M. L., Wang, L.-C., Means, T. K., & El Khoury, J. (2013) · Nature Neuroscience · doi:10.1038/nn.3554 · Cited by 1,511
Microglia-specific localisation of a novel calcium binding protein, Iba1
Ito, D., Imai, Y., Ohsawa, K., Nakajima, K., Fukuuchi, Y., & Kohsaka, S. (1998) · Molecular Brain Research · doi:10.1016/s0169-328x(98)00040-0 · Cited by 1,476 · cited 1×
“Since its first description in 1998 [3], IBA1 has been the most widely used marker for the immunohistochemical analysis of microglia.”
BackgroundIdentification of the platelet ADP receptor targeted by antithrombotic drugs
Hollopeter, G., Jantzen, H., Vincent, D., Li, G., England, L. J., Ramakrishnan, V., Yang, R., Nurden, P., Nurden, A. T., Julius, D. J., et al. (2001) · Nature · doi:10.1038/35051599 · Cited by 1,421 · cited 1×
“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].”
BackgroundSpatial and temporal heterogeneity of mouse and human microglia at single-cell resolution
Masuda, T., Sankowski, R., Staszewski, O., Böttcher, C., Amann, L., Sagar, Scheiwe, C., Nessler, S., Kunz, P., van Loo, G., et al. (2019) · Nature · doi:10.1038/s41586-019-0924-x · Cited by 1,310 · cited 1×
“Single-cell analysis demonstrated an increased expression of CD74 and HLA-DR in MS-associated microglial clusters [81], while a great variability in expression patterns displayed a high inter-individual heterogeneity of microglia in the different disease states.”
BackgroundMIF Signal Transduction Initiated by Binding to CD74
Leng, L., Metz, C. N., Fang, Y., Xu, J., Donnelly, S., Baugh, J., Delohery, T., Chen, Y., Mitchell, R. A., & Bucala, R. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030286 · Cited by 1,154 · cited 1×
“CD74 was characterized as a cell surface receptor for the macrophage migration inhibitory factor (MIF, [70,71]).”
BackgroundLi, Q., Cheng, Z., Zhou, L., Darmanis, S., Neff, N. F., Okamoto, J., Gulati, G., Bennett, M. L., Sun, L. O., Clarke, L. E., et al. (2019) · Neuron · doi:10.1016/j.neuron.2018.12.006 · Cited by 1,129
Hamza, T. H., Zabetian, C. P., Tenesa, A., Laederach, A., Montimurro, J. S., Yearout, D., Kay, D. M., Doheny, K. F., Paschall, J. E., Pugh, E., et al. (2010) · Nature Genetics · doi:10.1038/ng.642 · Cited by 808
Transcriptomic analysis of purified human cortical microglia reveals age-associated changes
Galatro, T. F., Holtman, I. R., Lerario, A. M., Vainchtein, I. D., Brouwer, N., Sola, P. R., Veras, M. M., Pereira, T. F., Leite, R. E. P., Möller, T., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4597 · Cited by 741 · cited 1×
“Human studies also detected a decrease in P2RY12 in senescent microglia [53,63].”
BackgroundStreit, W. J., Braak, H., Xue, Q.-S., & Bechmann, I. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0556-6 · Cited by 727 · cited 2×
“Dystrophic microglia, which appear to precede tau pathology [83], also stain positive for CD74 (Figure 1).”
BackgroundSelf-citationSingle cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease
Olah, M., Menon, V., Habib, N., Taga, M. F., Ma, Y., Yung, C. J., Cimpean, M., Khairallah, A., Coronas-Samano, G., Sankowski, R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19737-2 · Cited by 722 · cited 3×
“Recent experiments using deep sequencing revealed differences not only depending on the brain region, but also on age, gender, and pathology [28,39,99,102,108,109].”
BackgroundChiu, I. M., Morimoto, E. T. A., Goodarzi, H., Liao, J. T., O’Keeffe, S., Phatnani, H. P., Muratet, M., Carroll, M. C., Levy, S., Tavazoie, S., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.018 · Cited by 651
Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587 · cited 1×
“The triggering receptor expressed on myeloid cells (TREM)-2 serves as a binding partner for apolipoprotein E (APOE, [29]), and especially the ε4 allele has been shown to act as a risk factor for Alzheimer’s disease [30,31].”
BackgroundWalker, D. G., & Lue, L.-F. (2015) · Alzheimer's Research & Therapy · doi:10.1186/s13195-015-0139-9 · Cited by 562 · cited 4×
“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.”
BackgroundInfluentialKrabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., Miller, K. R., Prokop, S., Kettenmann, H., & Heppner, F. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060921 · Cited by 478
Valdearcos, M., Douglass, J. D., Robblee, M. M., Dorfman, M. D., Stifler, D. R., Bennett, M. L., Gerritse, I., Fasnacht, R., Barres, B. A., Thaler, J. P., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.015 · Cited by 477
Epigenetic regulation of brain region-specific microglia clearance activity
Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh, Y.-H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0192-3 · Cited by 460
TMEM119 marks a subset of microglia in the human brain
Satoh, J., Kino, Y., Asahina, N., Takitani, M., Miyoshi, J., Ishida, T., & Saito, Y. (2016) · Neuropathology · doi:10.1111/neup.12235 · Cited by 434 · cited 6×
“Despite being known as a homeostatic marker [45], several studies have shown a stable expression of TMEM119 also in response to injury and inflammatory conditions.”
BackgroundInfluentialAlzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation
Srinivasan, K., Friedman, B. A., Etxeberria, A., Huntley, M. A., van der Brug, M. P., Foreman, O., Paw, J. S., Modrusan, Z., Beach, T. G., Serrano, G. E., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107843 · Cited by 427 · cited 1×
“As shown in studies using single-cell RNA sequencing in Alzheimer’s disease and other neurodegenerative conditions, P2RY12 is one of the proteins marking the transition from homeostatic microglia to disease-associated microglia by the downregulation of gene expression [55,61].”
ResultMajor Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging
Soreq, L., Rose, J., Soreq, E., Hardy, J., Trabzuni, D., Cookson, M. R., Smith, C., Ryten, M., Patani, R., & Ule, J. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.011 · Cited by 419
Harms, A. S., Cao, S., Rowse, A. L., Thome, A. D., Li, X., Mangieri, L. R., Cron, R. Q., Shacka, J. J., Raman, C., & Standaert, D. G. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5610-12.2013 · Cited by 406
Iba1 Is an Actin-Cross-Linking Protein in Macrophages/Microglia
Sasaki, Y., Ohsawa, K., Kanazawa, H., Kohsaka, S., & Imai, Y. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5388 · Cited by 373 · cited 1×
“Although the exact function of IBA1 still needs to be elucidated, its involvement in phagocytosis is an accepted hypothesis [7].”
BackgroundFactors regulating microglia activation
Kierdorf, K., & Prinz, M. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00044 · Cited by 360 · cited 1×
“IRF8 is one of the intrinsic factors regulating the transition from a ramified to an activated microglial morphology [37,38].”
BackgroundIRF8 Is a Critical Transcription Factor for Transforming Microglia into a Reactive Phenotype
Masuda, T., Tsuda, M., Yoshinaga, R., Tozaki-Saitoh, H., Ozato, K., Tamura, T., & Inoue, K. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.02.014 · Cited by 338 · cited 1×
“IRF8 is one of the intrinsic factors regulating the transition from a ramified to an activated microglial morphology [37,38].”
BackgroundHendrickx, D. A. E., van Eden, C. G., Schuurman, K. G., Hamann, J., & Huitinga, I. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.04.007 · Cited by 313 · cited 3×
“Microglia expressing MHCII can present processed antigens to CD4-positive (CD4+) Tlymphocytes [27], and microglia upregulate HLA-DR in response to IFNγ stimulation [27].”
Backgroundvan der Poel, M., Ulas, T., Mizee, M. R., Hsiao, C.-C., Miedema, S. S. M., Adelia, Schuurman, K. G., Helder, B., Tas, S. W., Schultze, J. L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08976-7 · Cited by 306 · cited 1×
“Furthermore, the microglia in normal-appearing MS tissue were characterized by an unaltered expression of P2RY12 and TMEM119, demonstrating a preservation of microglial homeostatic functions and only localized changes [60].”
BackgroundChu, F., Shi, M., Zheng, C., Shen, D., Zhu, J., Zheng, X., & Cui, L. (2018) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2018.02.015 · Cited by 304 · cited 1×
“Upregulation was also described in different pathological conditions, such as MS [85] or traumatic brain injury [86].”
BackgroundMildner, A., Huang, H., Radke, J., Stenzel, W., & Priller, J. (2017) · Glia · doi:10.1002/glia.23097 · Cited by 301
Microglia actions in Alzheimer's disease
Prokop, S., Miller, K. R., & Heppner, F. L. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1182-x · Cited by 291
The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE
Guerreiro, R. J., Gustafson, D. R., & Hardy, J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.03.025 · Cited by 285 · cited 1×
“The triggering receptor expressed on myeloid cells (TREM)-2 serves as a binding partner for apolipoprotein E (APOE, [29]), and especially the ε4 allele has been shown to act as a risk factor for Alzheimer’s disease [30,31].”
BackgroundThe multifaceted roles of the invariant chain CD74 — More than just a chaperone
Schröder, B. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.03.026 · Cited by 284
Hormones and diet, but not body weight, control hypothalamic microglial activity
Gao, Y., Ottaway, N., Schriever, S. C., Legutko, B., García‐Cáceres, C., de la Fuente, E., Mergen, C., Bour, S., Thaler, J. P., Seeley, R. J., et al. (2013) · Glia · doi:10.1002/glia.22580 · Cited by 263
Expression of CD68 in Non‐Myeloid Cell Types
Gottfried, E., Kunz‐Schughart, L. A., Weber, A., Rehli, M., Peuker, A., Müller, A., Kastenberger, M., Brockhoff, G., Andreesen, R., & Kreutz, M. P. (2008) · Scandinavian Journal of Immunology · doi:10.1111/j.1365-3083.2008.02091.x · Cited by 261
Shaping Neuronal Fate: Functional Heterogeneity of Direct Microglia-Neuron Interactions
Cserép, C., Pósfai, B., & Dénes, Á. (2021) · Neuron · doi:10.1016/j.neuron.2020.11.007 · Cited by 256
Doorn, K. J., Moors, T., Drukarch, B., van de Berg, W. D., Lucassen, P. J., & van Dam, A.-M. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0090-1 · Cited by 254
Neumann, H., & Takahashi, K. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.11.032 · Cited by 249 · cited 1×
“Furthermore, it was demonstrated that TREM2 increases phagocytosis and secretion of anti-inflammatory cytokines [33].”
BackgroundRegulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS
Illés, P., Rubini, P., Ulrich, H., Zhao, Y., & Tang, Y. (2020) · Cells · doi:10.3390/cells9051108 · Cited by 249 · cited 1×
“On the other hand, the density of P2RY12 is modified depending on the microglial activation state [54].”
BackgroundTREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice
Frank, S., Burbach, G. J., Bonin, M., Walter, M., Streit, W., Bechmann, I., & Deller, T. (2008) · Glia · doi:10.1002/glia.20710 · Cited by 247 · cited 1×
“We have shown that TREM2 is the highest upregulated mRNA in microdissected periplaque areas [32].”
BackgroundSelf-citationHigh-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia
Baufeld, C., Osterloh, A., Prokop, S., Miller, K. R., & Heppner, F. L. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1595-4 · Cited by 246
Long-Range Ca2+ Waves Transmit Brain-Damage Signals to Microglia
Sieger, D., Moritz, C., Ziegenhals, T., Prykhozhij, S. V., & Peri, F. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.04.012 · Cited by 231 · cited 1×
“[58] demonstrated that the knockdown of P2RY12 in zebrafish led to a complete block of the microglial response to injury.”
BackgroundSpencer, S. J., D’Angelo, H. M., Soch, A., Watkins, L. R., Maier, S. F., & Barrientos, R. M. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.06.014 · Cited by 223
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Microglia and Neuroinflammation: What Place for P2RY12?
Gómez Morillas, A., Besson, V. C., & Lerouet, D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041636 · Cited by 214 · cited 2×
“As shown in studies using single-cell RNA sequencing in Alzheimer’s disease and other neurodegenerative conditions, P2RY12 is one of the proteins marking the transition from homeostatic microglia to disease-associated microglia by the downregulation of gene expression [55,61].”
BackgroundResultP2Y12 expression and function in alternatively activated human microglia
Moore, C. S., Ase, A. R., Kinsara, A., Rao, V. T. S., Michell-Robinson, M., Leong, S. Y., Butovsky, O., Ludwin, S. K., Séguéla, P., Bar-Or, A., et al. (2015) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000080 · Cited by 212 · cited 1×
“Stimulation of P2RY12 triggers the initial extension of microglial processes towards the site of injury [55,56].”
BackgroundAcute and non-resolving inflammation associate with oxidative injury after human spinal cord injury
Zrzavy, T., Schwaiger, C., Wimmer, I., Berger, T., Bauer, J., Butovsky, O., Schwab, J. M., Lassmann, H., & Höftberger, R. (2020) · Brain · doi:10.1093/brain/awaa360 · Cited by 212 · cited 2×
“[46], detected a return of low numbers of P2RY12-positive cells in the late stages of the injury process in human spinal cord injury.”
BackgroundAssociation of Parkinson Disease with Structural and Regulatory Variants in the HLA Region
Wissemann, W. T., Hill-Burns, E. M., Zabetian, C. P., Factor, S. A., Patsopoulos, N., Hoglund, B., Holcomb, C., Donahue, R. J., Thomson, G., Erlich, H., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.10.009 · Cited by 189
Koizumi, S., Ohsawa, K., Inoue, K., & Kohsaka, S. (2013) · Glia · doi:10.1002/glia.22358 · Cited by 184 · cited 1×
“therefore leads to morphological activation [57].”
Iron loading is a prominent feature of activated microglia in Alzheimer’s disease patients
Kenkhuis, B., Somarakis, A., de Haan, L., Dzyubachyk, O., IJsselsteijn, M. E., de Miranda, N. F. C. C., Lelieveldt, B. P. F., Dijkstra, J., van Roon-Mom, W. M. C., Höllt, T., et al. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01126-5 · Cited by 184 · cited 1×
“[47] demonstrated a microglial subset with an increased expression of the iron storage protein ferritin light chain (FTL) and IBA1, while exhibiting a decrease in TMEM119 and P2RY12 expression.”
BackgroundPeferoen, L. A. N., Vogel, D. Y. S., Ummenthum, K., Breur, M., Heijnen, P. D. A. M., Gerritsen, W. H., Peferoen-Baert, R. M. B., van der Valk, P., Dijkstra, C. D., & Amor, S. (2015) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000149 · Cited by 178 · cited 3×
“[74] suggested that CD74 expression represents a pro-inflammatory state.”
BackgroundMicroglia activation in hepatic encephalopathy in rats and humans
Zemtsova, I. M., Görg, B., Keitel, V., Bidmon, H. J., Schrör, K., & Häussinger, D. (2011) · Hepatology · doi:10.1002/hep.24326 · Cited by 178
MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis
Ghoochani, A., Schwarz, M. A., Yakubov, E., Engelhorn, T., Doerfler, A., Buchfelder, M., Bucala, R., Savaskan, N. E., & Eyüpoglu, I. Y. (2016) · Oncogene · doi:10.1038/onc.2016.160 · Cited by 168 · cited 2×
“Similarly, CD74-silenced microglial cells presented an elevation in IFNγ levels [73].”
BackgroundRole of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair
Farr, L., Ghosh, S., & Moonah, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01273 · Cited by 166
Lue, L., Schmitz, C. T., Serrano, G., Sue, L. I., Beach, T. G., & Walker, D. G. (2015) · Brain Pathology · doi:10.1111/bpa.12190 · Cited by 154 · cited 1×
“[34] detected an upregulation of IBA1 in association with TREM2 levels in the temporal cortex of Alzheimer disease patients.”
BackgroundCD74 is a novel transcription regulator
Gil-Yarom, N., Radomir, L., Sever, L., Kramer, M. P., Lewinsky, H., Bornstein, C., Blecher-Gonen, R., Barnett-Itzhaki, Z., Mirkin, V., Friedlander, G., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612195114 · Cited by 153
Dystrophic microglia in late‐onset Alzheimer's disease
Streit, W. J., Khoshbouei, H., & Bechmann, I. (2020) · Glia · doi:10.1002/glia.23782 · Cited by 152
Self-citationvan Wageningen, T. A., Vlaar, E., Kooij, G., Jongenelen, C. A. M., Geurts, J. J. G., & van Dam, A.-M. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0850-z · Cited by 147 · cited 4×
“In contrast, MHCII-positive cells in non-active white matter lesions stained positive for not only IBA1 and P2RY12, but also TMEM119 [12].”
BackgroundInfluentialCD74 Is a Member of the Regulated Intramembrane Proteolysis-processed Protein Family
Becker-Herman, S., Arie, G., Medvedovsky, H., Kerem, A., & Shachar, I. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-04-0327 · Cited by 141
Walker, D. G., Tang, T. M., Mendsaikhan, A., Tooyama, I., Serrano, G. E., Sue, L. I., Beach, T. G., & Lue, L.-F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020678 · Cited by 128 · cited 1×
“Similar results were shown by Walker and colleagues, who demonstrated that P2RY12 expression differed depending on the types of plaques or tangles they were associated with [64].”
ResultInhomogeneous distribution of Iba‐1 characterizes microglial pathology in Alzheimer's disease
Tischer, J., Krueger, M., Mueller, W. C., Staszewski, O., Prinz, M., Streit, W. J., & Bechmann, I. (2016) · Glia · doi:10.1002/glia.23024 · Cited by 121 · cited 2×
“In immune histochemical analysis, one needs to distinguish between a discontinuous expression of IBA1, due to shrinkage of the microglial processes, as described as a hallmark characteristic of senescent microglia [40], and an IBA1-negative microglial phenotype.”
BackgroundSelf-citationKöhler, C. (2007) · Cell and Tissue Research · doi:10.1007/s00441-007-0474-7 · Cited by 120
Bulk, M., Abdelmoula, W. M., Nabuurs, R. J. A., van der Graaf, L. M., Mulders, C. W. H., Mulder, A. A., Jost, C. R., Koster, A. J., van Buchem, M. A., Natté, R., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.10.017 · Cited by 118 · cited 1×
“[25] demonstrated an association between an advanced disease state in patients suffering from Huntington’s disease and IBA1-negative microglia.”
BackgroundExpression of CD74 is increased in neurofibrillary tangles in Alzheimer's disease
Bryan, K. J., Zhu, X., Harris, P. L., Perry, G., Castellani, R. J., Smith, M. A., & Casadesus, G. (2008) · Molecular Neurodegeneration · doi:10.1186/1750-1326-3-13 · Cited by 114 · cited 2×
“However, human microglia in all morphological states show a distinct expression of CD74 (Figure 1, [76]), pointing to a potentially important species difference.”
BackgroundGraham, L. C., Harder, J. M., Soto, I., de Vries, W. N., John, S. W. M., & Howell, G. R. (2016) · Scientific Reports · doi:10.1038/srep21568 · Cited by 113 · cited 1×
“While most studies have focused on the rodent hypothalamus [15–17], microglial activation, and therefore an increased appearance of IBA1 in rodent hippocampi was only detected after imitating the effects of a long-term (eight month) Western diet on mice [18].”
BackgroundZeiner, P. S., Preuße, C., Blank, A., Zachskorn, C., Baumgarten, P., Caspary, L., Braczynski, A. K., Weissenberger, J., Bratzke, H., Reiß, S., et al. (2014) · Brain Pathology · doi:10.1111/bpa.12194 · Cited by 109 · cited 4×
“The binding of MIF to CD74 leads to an increased recruitment of macrophages and dendritic cells [72].”
BackgroundInfluentialSubbarayan, M. S., Hudson, C., Moss, L. D., Nash, K. R., & Bickford, P. C. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01911-4 · Cited by 107
TREM2 triggers microglial density and age-related neuronal loss
Linnartz‐Gerlach, B., Bodea, L., Klaus, C., Ginolhac, A., Halder, R., Sinkkonen, L., Walter, J., Colonna, M., & Neumann, H. (2019) · Glia · doi:10.1002/glia.23563 · Cited by 104 · cited 1×
“This observation was visible at every timepoint tested and even increased with age [35].”
BackgroundMinten, C., Terry, R., Deffrasnes, C., King, N. J. C., & Campbell, I. L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049851 · Cited by 100 · cited 1×
“However, experiments using interferon regulatory factor 8 (IRF8)-deficient microglia [36], showed significantly reduced levels of IBA1, but no deficits in phagocytosis.”
MethodMicroglial activation occurs late during preclinical Alzheimer's disease
Streit, W. J., Braak, H., Del Tredici, K., Leyh, J., Lier, J., Khoshbouei, H., Eisenlöffel, C., Müller, W., & Bechmann, I. (2018) · Glia · doi:10.1002/glia.23510 · Cited by 98
Self-citationSwanson, M. E. V., Scotter, E. L., Smyth, L. C. D., Murray, H. C., Ryan, B., Turner, C. P., Faull, R. L. M., Dragunow, M., & Curtis, M. A. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01047-9 · Cited by 91 · cited 1×
“IBA1-low populations were detected in the human Alzheimer disease cortex [26], while simultaneously showing increased levels of—amongst others—ferritin, CD74 and CD45.”
BackgroundPatir, A., Shih, B., McColl, B. W., & Freeman, T. C. (2019) · Glia · doi:10.1002/glia.23572 · Cited by 90
van Olst, L., Rodriguez-Mogeda, C., Picon, C., Kiljan, S., James, R. E., Kamermans, A., van der Pol, S. M. A., Knoop, L., Michailidou, I., Drost, E., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02293-4 · Cited by 87 · cited 2×
“[97] demonstrated no increased expression of CD68 in multiple sclerosis, therefore emphasizing the importance of using several markers in order to describe the microglial phenotypes as thoroughly as possible.”
BackgroundMacrosialin increases during normal brain aging are attenuated by caloric restriction
Wong, A. M., Patel, N. V., Patel, N. K., Wei, M., Morgan, T. E., de Beer, M. C., de Villiers, W. J. S., & Finch, C. E. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.07.058 · Cited by 85 · cited 5×
“Furthermore, CD74 was significantly increased in IFNγ-stimulated cultured human microglia [74], suggesting a feedback mechanism and, therefore, an important role of CD74 in IFNγ signaling.”
BackgroundInfluentialThe Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease
Bonham, L. W., Sirkis, D. W., & Yokoyama, J. S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01170 · Cited by 83 · cited 1×
“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].”
BackgroundFatty food, fatty acids, and microglial priming in the adult and aged hippocampus and amygdala
Butler, M. J., Cole, R. M., Deems, N. P., Belury, M. A., & Barrientos, R. M. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.06.010 · Cited by 82 · cited 1×
“Moreover, MHCII gene expression is increased in the aged rodent hippocampus, and even more potently by the addition of a high-fat diet (HFD, [87,88]).”
BackgroundMaeda, J., Minamihisamatsu, T., Shimojo, M., Zhou, X., Ono, M., Matsuba, Y., Ji, B., Ishii, H., Ogawa, M., Akatsu, H., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcab011 · Cited by 80 · cited 2×
“A reduction in P2RY12 immunoreactivity in the microglia was observed prior to massive accumulations of phosphorylated tau protein and neurodegeneration in rTg4510 mouse brains, despite a progressive increase in the total microglial population [62].”
BackgroundP2Y12Receptor on the Verge of a Neuroinflammatory Breakdown
Amadio, S., Parisi, C., Montilli, C., Carrubba, A. S., Apolloni, S., & Volonté, C. (2014) · Mediators of Inflammation · doi:10.1155/2014/975849 · Cited by 73 · cited 1×
“Due to the decrease in its expression in an activated microglial status, P2RY12 is usually described as a homeostatic marker [53,59].”
BackgroundXue, F., & Du, H. (2021) · Cells · doi:10.3390/cells10020321 · Cited by 73 · cited 8×
“Lue et al. [34] detected an upregulation of IBA1 in association with TREM2 levels in the temporal cortex of Alzheimer disease patients.”
BackgroundInfluentialEvidence for More than One Parkinson's Disease-Associated Variant within the HLA Region
Hill‐Burns, E. M., Factor, S. A., Zabetian, C. P., Thomson, G. J., & Payami, H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027109 · Cited by 71
Characterization of human monocyte‐derived microglia‐like cells
Leone, C., Le Pavec, G., Même, W., Porcheray, F., Samah, B., Dormont, D., & Gras, G. (2006) · Glia · doi:10.1002/glia.20372 · Cited by 70
A loss of mature microglial markers without immune activation in schizophrenia
Snijders, G. J. L., van Zuiden, W., Sneeboer, M. A. M., van Berlekom, A. B., van der Geest, A. T., Schnieder, T. P., MacIntyre, D. J., Hol, E. M., Kahn, R. S., & de Witte, L. D. (2021) · Glia · doi:10.1002/glia.23962 · Cited by 70
Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy
Dennis, C. V., Sheahan, P. J., Graeber, M. B., Sheedy, D. L., Kril, J. J., & Sutherland, G. T. (2013) · Metabolic Brain Disease · doi:10.1007/s11011-013-9469-0 · Cited by 69 · cited 1×
“[22], demonstrated a decrease in IBA1 expression in a subtype of hepatic encephalopathy (HE), which they called non-proliferative HE.”
Background(1995) · PubMed Central · Cited by 65
Expression of CD74 in high grade gliomas: a potential role in temozolomide resistance
Kitange, G. J., Carlson, B. L., Schroeder, M. A., Decker, P. A., Morlan, B. W., Wu, W., Ballman, K. V., Giannini, C., & Sarkaria, J. N. (2010) · Journal of Neuro-Oncology · doi:10.1007/s11060-010-0186-9 · Cited by 56 · cited 1×
“The activation of CD74 inhibits microglial migration and therefore, invasion into the tumor [73,77].”
BackgroundMeza‐Romero, R., Benedek, G., Yu, X., Mooney, J. L., Dahan, R., Duvshani, N., Bucala, R., Offner, H., Reiter, Y., Burrows, G. G., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1303118 · Cited by 54 · cited 1×
“In cases of MS, CD74 was expressed in pre-active and remyelinating lesions [74], and interestingly, blocking CD74 in an experimental autoimmune encephalomyelitis (EAE) model ameliorated the symptoms in mice [79].”
BackgroundThe G protein-coupled receptor GPR34 – The past 20 years of a grownup
Schöneberg, T., Meister, J., Knierim, A. B., & Schulz, A. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.04.008 · Cited by 54 · cited 1×
“Genetic targeting of TREM2 induced the restored expression of homeostatic microglial markers, such as TMEM119 and P2RY12, concomitant with the G-proteincoupled receptor (GPR)-34 [49], which is necessary for keeping microglial morphology in a homeostatic non-phagocytic phenotype [50].”
BackgroundExtracellular microvesicles promote microglia‐mediated pro‐inflammatory responses to ethanol
Crews, F. T., Zou, J., & Coleman, L. G. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24813 · Cited by 54 · cited 1×
“In primary organotypic brain slice cultures, ethanol caused a unique immune gene signature with a reduction in Tmem119 and a progressive increase in P2RY12 [65], suggesting a distinct microglial phenotype following ethanol treatment.”
BackgroundRegulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS
Illes, P., Rubini, P., Ulrich, H., et al. (2020) · doi:10.20944/preprints202003.0288.v1 · Cited by 54
Partial MHC class II constructs inhibit MIF / CD 74 binding and downstream effects
Benedek, G., Meza‐Romero, R., Andrew, S. F., Leng, L., Burrows, G. G., BOURDETTE, D. N., Offner, H., Bucala, R., & Vandenbark, A. A. (2013) · European Journal of Immunology · doi:10.1002/eji.201243162 · Cited by 53 · cited 1×
“Furthermore, higher levels of CD74 in monocytes were observed in patients with MS compared to controls [80].”
BackgroundGzielo, K., Kielbinski, M., Ploszaj, J., Janeczko, K., Gazdzinski, S. P., & Setkowicz, Z. (2017) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-016-0417-5 · Cited by 48 · cited 1×
“[19] showed that the area fraction covered by IBA1-positive cells was reduced after consumption for one year.”
BackgroundIves, A., Roy, D. L., Théroude, C., Bernhagen, J., Roger, T., & Calandra, T. (2021) · The FASEB Journal · doi:10.1096/fj.202001605r · Cited by 47 · cited 1×
“The binding of MIF to CD74 leads to an increased recruitment of macrophages and dendritic cells [72].”
BackgroundMurata, Y., Sugimoto, K., Yang, C., Harada, K., Gono, R., Harada, T., Miyashita, Y., Higashisaka, K., Katada, R., Tanaka, J., et al. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104848 · Cited by 44 · cited 1×
“The IBA1 mRNA levels were increased in the peri-infarct tissue and the ischemic core [14], while IBA1-positive cells also expressed the pro-inflammatory cytokines TNFα and interleukin-1α [14].”
BackgroundHwang, I. K., Park, J. H., Lee, T.-K., Kim, D. W., Yoo, K., Ahn, J. H., Kim, Y. H., Cho, J. H., Kim, Y., Won, M., et al. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6525 · Cited by 43 · cited 1×
“In rodents, CD74 immunoreactivity was not observed in the hippocampus until three days post-ischemia [75].”
BackgroundExpression of invariant chain and pro-cathepsin L in Alzheimer's brain
Yoshiyama, Y., Arai, K., Oki, T., & Hattori, T. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01326-4 · Cited by 37 · cited 1×
“[82] detected an increase in CD74 in AD microglia.”
BackgroundHLA Typing and Parkinson’s Disease
Lampe, J. B., Goßrau, G., Herting, B., Kempe, A., Sommer, U., Füssel, M., Weber, M., Koch, R., & Reichmann, H. (2003) · European Neurology · doi:10.1159/000072500 · Cited by 34
Amaya, J. M., Suidgeest, E., Sahut‐Barnola, I., Dumontet, T., Montanier, N., Pagés, G., Keller, C., van der Weerd, L., Pereira, A. M., Martinez, A., et al. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.604103 · Cited by 34 · cited 1×
“In rodents, another metabolic condition was shown to have an impact on microglial IBA1 expression: In the cingulate regions of the anterior corpus callosum and the hippocampus, a decrease in IBA1 expression was observed in long-term hypercorticosteronemia [23].”
BackgroundFast microglial activation after severe traumatic brain injuries
Lier, J., Ondruschka, B., Bechmann, I., & Dreßler, J. (2020) · International Journal of Legal Medicine · doi:10.1007/s00414-020-02308-x · Cited by 33 · cited 1×
“Upregulation was also described in different pathological conditions, such as MS [85] or traumatic brain injury [86].”
Self-citationKannarkat, G. T., Lee, J.-K., Ramsey, C. P., Chung, J., Chang, J., Porter, I., Oliver, D. L., Shepherd, K. R., & Tansey, M. G. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.02.006 · Cited by 26
Loss of IBA1-Expression in brains from individuals with obesity and hepatic dysfunction
Lier, J., Winter, K., Bleher, J., Grammig, J., Mueller, W. C., Streit, W., & Bechmann, I. (2019) · Brain Research · doi:10.1016/j.brainres.2019.01.006 · Cited by 26
Self-citationJimenez-Ferrer, I., Bäckström, F., Dueñas-Rey, A., Jewett, M., Boza-Serrano, A., Luk, K. C., Deierborg, T., & Swanberg, M. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.10.017 · Cited by 26 · cited 1×
“This suggests an active involvement of these cells in the clearing of α-synuclein [94].”
BackgroundMichalski, D., Pitsch, R., Pillai, D. R., Mages, B., Aleithe, S., Grosche, J., Martens, H., Schlachetzki, F., & Härtig, W. (2017) · PLOS ONE · doi:10.1371/journal.pone.0174996 · Cited by 15 · cited 1×
“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].”
BackgroundMicroglial Proliferation in Obesity: When, Where, Why, and What Does It Mean?
Chowen, J. A., Horváth, T. L., & Argente, J. (2017) · Diabetes · doi:10.2337/dbi16-0073 · Cited by 2
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Green, T. R. F., & Rowe, R. K. (2024) · Clinical & Experimental Immunology · doi:10.1093/cei/uxae023 · Cited by 119
“Microglial reactivity is controlled by many coordinated factors; microglia express multiple cell surface receptors that regulate cell signaling and, in turn, microglial gene expression [8, 9].”
BackgroundRoles of microglia in adult hippocampal neurogenesis in depression and their therapeutics
Fang, S., Wu, Z., Guo, Y., Zhu, W., Wan, C., Yuan, N., Chen, J., Hao, W., Mo, X., Guo, X., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1193053 · Cited by 107
“There are three main activated microglial morphotypes in current reports: hyper-rami fi ed, phagocytic, and amoeboid types (47 – 49).”
BackgroundLi, J., Wang, H., Liu, D., Li, X., He, L., Pan, J., Shen, Q., & Peng, Y. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.02.001 · Cited by 92
“The extent of these morphological changes is closely related to microglial functions other than cytokine release, such as synapse pruning and phagocytosis (Lier et al., 2021).”
The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes
West, P. K., McCorkindale, A. N., Guennewig, B., Ashhurst, T. M., Viengkhou, B., Hayashida, E., Jung, S. R., Butovsky, O., Campbell, I. L., & Hofer, M. J. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02441-x · Cited by 79
Regulation of microglia polarization after cerebral ischemia
Wang, H., Li, J., Zhang, H., Wang, M., Xiao, L., Wang, Y., & Cheng, Q. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1182621 · Cited by 81
“Inhibition of CysLTR1 or CysLTR2 protects against LPS or ischemia-induced microglial inflammation and brain injury (Shi et al., 2015; Chen F. et al., 2017; Lin et al., 2017).”
Background
Metadata
- Authors
- Lier, J., Streit, W. J., & Bechmann, I.
- Affiliations
- Leipzig University (DE)
- University of Florida Health (US)
- Corresponding author
- Lier, Julia
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2021-08-28
- Volume
- 10
- Issue
- 9
- Pages
- 2236
- ISSN
- 2073-4409 (ISSN-L)
- 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
- gold
- doi.org
- 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
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.
A language model drew the claims from the paper on 2026-10-13, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-13 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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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