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Cited by 1,046Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesNeuroscience and Neuropharmacology Research

Microglial signatures and their role in health and disease

Open access
Butovsky, Oleg, Weiner, Howard L.·2018·Nature Reviews Neuroscience
DOI 10.1038/s41583-018-0057-5PMC PMC7255106
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Abstract

Microglia are the primary innate immune cells in the CNS. In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages. In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment. Technological advances have allowed the molecular ‘signatures’ of microglia to be characterized, providing insight into their roles in CNS function. Weiner and Butovsky discuss the plasticity of these signatures in health and disease and consider the mechanisms underlying their establishment, maintenance and regulation.

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  • Premisecitation

    In the healthy brain, microglia have a unique homeostatic molecular signature, comprising a distinct transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages.

    “In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [25] Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).This study identifies the molecular and functional signature of homeostatic microglia, which depends on TGFβ signalling. source

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    • cites [27] Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). source

      Not checked in the free run.

    • cites [28] Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013). source

      Not checked in the free run.

    • cites [29] Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012). source

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    Microglia, but not peripheral myeloid cells, express P2ry12, Tmem119, Siglech, Gpr34, Socs3, Hexb, Olfml3, and Fcrls.

    “microglia — but not peripheral myeloid cells — were shown to express P2Y purinoceptor 12 (P2ry12), transmembrane protein 119 (Tmem119), sialic acid binding Ig-like lectin H (Siglech), probable G protein coupled receptor 34 (Gpr34), suppressor of cytokine signalling 3 (Socs3), β-hexosaminidase subunit β (Hexb), olfactomedin-like protein 3 (Olfml3) and Fc receptor-like S, scavenger receptor (Fcrls).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [25] Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).This study identifies the molecular and functional signature of homeostatic microglia, which depends on TGFβ signalling. source

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    • cites [27] Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). source

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    • cites [28] Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013). source

      Not checked in the free run.

    • cites [29] Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012). source

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    In some circumstances, peripherally derived macrophages can replace depleted microglia with cells that maintain a distinct identity from microglia.

    “in some circumstances, peripherally derived macrophages can replace depleted microglia with cells that maintain their own unique identity (distinct from that of microglia)17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Cronk, J. C. et al. Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J. Exp. Med. https://doi.org/10.1084/jem.20180247 (2018).This study shows that microglial populations can be replaced with peripherally derived macrophages that maintain a unique identity and distinct functional role in the CNS compared with microglia. source

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  • Premisecitation

    Microglia express macrophage markers including ADGRE/F4/80, Fc receptors, and ITGAM/CD11b in mice and humans.

    “Microglia express macrophage markers, including adhesion G protein-coupled receptor E1 (ADGRE; also known as cell surface glycoprotein F4/80), crystallizable fragment (Fc) receptors, and αM integrin (ITGAM; also known as CD11b), in mice41 and in humans42.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Perry, V. H., Hume, D. A. & Gordon, S. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15, 313–326 (1985). source

      Not checked in the free run.

    • cites [42] Akiyama, H. & McGeer, P. L. Brain microglia constitutively express beta-2 integrins. J. Neuroimmunol. 30, 81–93 (1990). source

      Not checked in the free run.

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    In adulthood, microglia are an independent self-renewing population.

    “in adulthood, microglia are an independent self-renewing population12–14”
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    • cites [12] Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015). This study reports that microglia have the potential to self-renew without the need for a contribution of peripheral myeloid cells. source

      Not checked in the free run.

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

      Not checked in the free run.

    • cites [14] Askew, K. et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 18, 391–405 (2017).References 13 and 14 show that microglia self-renew stochastically in the healthy brain and expand clonally during disease. The resulting excess in microglia is resolved by cell egress and programmed cell death. source

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    Premisecitation

    Microglia exist in resting or activated states depending on the inflammatory milieu, which differs between the healthy CNS and disease states.

    “Microglia exist in resting or activated states depending on the inflammatory milieu, which differs in the healthy CNS and in various disease states19–22.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [19] Ransohoff, R. M. & Cardona, A. E. The myeloid cells of the central nervous system parenchyma. Nature 468, 253–262 (2010). source

      Not checked in the free run.

    • cites [20] Kettenmann, H., Hanisch, U. K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011). source

      Not checked in the free run.

    • cites [21] Hanisch, U. K. & Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387–1394 (2007). source

      Not checked in the free run.

    • cites [22] Hanisch, U. K. Functional diversity of microglia - how heterogeneous are they to begin with? Front. Cell. Neurosci. 7, 65 (2013). source

      Not checked in the free run.

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    Premisecitation

    Mouse microglia show region-specific transcriptional profiles and age-dependent regional variability, and cerebellar and hippocampal microglia exist in a more immune-vigilant state than forebrain microglia.

    “a genome-wide analysis of gene expression in microglia from different brain regions across the adult lifespan of the mouse was performed found that there are region-specific transcriptional profiles and age-dependent regional variability in gene expression59.”
    • Also stated in: § Microglial heterogeneity and plasticity · hedged
      “The findings further suggested that cerebellar and hippocampal microglia exist in a more ‘immune-vigilant’ state than microglia in forebrain regions.”
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    • cites [59] Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).This study describes the age-dependent and region-dependent transcriptional heterogeneity of microglia. source

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    Premisecitation

    During inflammation, microglia change from a bushy shape with extended processes to an amoeboid shape and produce inflammatory factors.

    “during inflammation, microglia change from a ‘bushy’ shape with extended processes to become amoeboid and produce inflammatory factors62,63.”
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    • cites [62] Ladeby, R. et al. Microglial cell population dynamics in the injured adult central nervous system. Brain Res. Rev. 48, 196–206 (2005). source

      Not checked in the free run.

    • cites [63] Ziebell, J. M., Adelson, P. D. & Lifshitz, J. Microglia: dismantling and rebuilding circuits after acute neurological injury. Metab. Brain Dis. 30, 393–400 (2015). source

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    Premisecitation

    Distinguishing cell types by relative surface marker expression using flow cytometry has limitations, and CD45 is upregulated on microglia associated with Aβ plaques in the APP/PS1 AD mouse model.

    “this method of distinguishing between cell types relies on relative surface marker expression as assessed by flow cytometry, which can have some limitations. For example, CD45 surface expression is known to be upregulated on microglia associated with amyloid-β (Aβ) plaques in the APP/PS1 mouse model of Alzheimer disease (AD)52.”
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    • cites [52] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).This study identifies a major microglial neurodegenerative phenotype in rodent and humans regulated by TREM2–ApoE signalling. source

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    Premisecitation

    SIGLEC1/CD169 is not expressed in microglia in health or disease and has been proposed as a marker for invading monocyte-derived macrophages in the CNS.

    “sialoadhesin (SIGLEC1; also known as CD169) is a marker for mature dendritic cells and macrophages in both mice and humans48 and has been proposed as a marker for invading monocyte-derived macrophages in the CNS as it is not expressed in microglia in health or disease49–52.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [48] Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013). source

      Not checked in the free run.

    • cites [49] Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012).This study shows the relevance of innate inflammation for ALS pathogenesis and identifies miR-155 as a potential therapeutic target. source

      Not checked in the free run.

    • cites [50] Gao, L. et al. Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice. J. Exp. Med. 212, 469–480 (2015). source

      Not checked in the free run.

    • cites [51] Zondler, L. et al. Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol. 132, 391–411 (2016). source

      Not checked in the free run.

    • cites [52] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).This study identifies a major microglial neurodegenerative phenotype in rodent and humans regulated by TREM2–ApoE signalling. source

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    Premisecitation

    Human microglia turn over at a median yearly rate of 28% and live on average for 4.2 years.

    “Human microglia turn over at a yearly median rate of 28% and live, on average, for 4.2 years.”
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    • cites [15] Reu, P. et al. The lifespan and turnover of microglia in the human brain. Cell Rep. 20, 779–784 (2017). source

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    Premisecitation

    Not all microglia express TREM2 in several CNS areas, and TREM2 mutations are a risk factor for non-familial AD.

    “not all microglia express triggering receptor expressed on myeloid cells 2 (TREM2)57, an immune receptor that is found in brain microglia and, when mutated, is a risk factor for non-familial AD58.”
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    • cites [57] Schmid, C. D. et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J. Neurochem. 83, 1309–1320 (2002). source

      Not checked in the free run.

    • cites [58] Colonna, M. & Wang, Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 17, 201–207 (2016). source

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    Premisecitation

    Microglia originate from mesodermal progenitors that colonize the CNS early and arise from the yolk sac.

    “The origin of microglia has now been clearly defined and shown to relate to the early colonization of the CNS by mesodermal progenitors6 that arise from the yolk sac7,8”
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    • cites [6] Kaur, C., Hao, A. J., Wu, C. H. & Ling, E. A. Origin of microglia. Microsc. Res. Tech. 54, 2–9 (2001). source

      Not checked in the free run.

    • cites [7] Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145–152 (1999). source

      Not checked in the free run.

    • cites [8] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).References 7 and 8 identify microglia as originating from yolk-sac-derived primitive macrophages. source

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    Premisecitation

    Microglia express lower CD45 than monocytes, allowing discrimination, and CD163 expression distinguishes microglia from perivascular macrophages.

    “microglia express lower levels of receptor-type tyrosine-protein phosphatase C (PTPRC; also known as CD45) than monocytes, allowing these two cell types to be discriminated, whereas the expression of scavenger receptor cysteine-rich type 1 protein M130 (CD163) by microglia enables their distinction from perivascular macrophages35,44–47.”
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    • cites [35] Bennett, M. L. et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl Acad. Sci. USA 113, E1738–E1746 (2016). source

      Not checked in the free run.

    • cites [44] Vainchtein, I. D. et al. In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed. Glia 62, 1724–1735 (2014). source

      Not checked in the free run.

    • cites [45] van den Berg, T. K., Puklavec, M. J., Barclay, A. N. & Dijkstra, C. D. Monoclonal antibodies against rat leukocyte surface antigens. Immunol. Rev. 184, 109–116 (2001). source

      Not checked in the free run.

    • cites [46] Kim, W. K. et al. CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am. J. Pathol. 168, 822–834 (2006). source

      Not checked in the free run.

    • cites [47] Sousa, C., Biber, K. & Michelucci, A. Cellular and molecular characterization of microglia: a unique immune cell population. Front. Immunol. 8, 198 (2017).

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    Interpretationreasoning

    In AD, the ability of microglia to prune excess synapses in development is inappropriately activated and participates in synapse loss.

    “These findings suggest that, in AD, the ability of microglia to prune excess synapses in development is inappropriately activated and participates in synapse loss.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Microglial development depends on CSF1R and on IRF8, which is essential for development of mature A2 microglial precursors.

    “the development of microglia is dependent on CSF1R, which transmits signals upon activation by its ligands CSF1 and IL-34 and serves as a survival factor68.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “It has also been shown that the development of microglia relies on the secondary transcription factor IFN regulatory factor 8 (IRF8), which is essential for the development of the mature microglia precursors known as A2 cells10”
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    • cites [68] Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012). source

      Not checked in the free run.

    • cites [10] Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).This study shows that microglia derived from erythromyeloid precursors develop into CD45 + c-kit lo CX 3 CR1 – immature (A1) cells and mature into CD45 + c-kit – CX 3 CR1 + (A2) cells. Both PU.1 and IRF8 transcription factors are vital for the development of A2 microglia. source

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    Premisecitation

    MEF2C suppresses the inflammatory response in homeostatic microglia, its expression declines during ageing in an IFN-1-dependent manner, and loss of microglial MEF2C is linked to CX3CR1 downregulation.

    “the transcription factor MEF2C acts in homeostatic microglia to suppress the inflammatory response and that its expression declines during ageing in an interferon (IFN)-1-dependent manner77.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “This study showed that loss of microglial MEF2C was linked to downregulation of CX3CR1, a molecule that is crucial for restraining immune responses in microglia78,79.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [77] Deczkowska, A. et al. Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner. Nat. Commun. 8, 717 (2017). source

      Not checked in the free run.

    • cites [78] Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917–924 (2006). source

      Not checked in the free run.

    • cites [79] Limatola, C. & Ransohoff, R. M. Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front. Cell. Neurosci. 8, 229 (2014). source

      Not checked in the free run.

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    Premisecitation

    CNS-conditional Tgfb1−/− mice exhibit motor deficits, loss of homeostatic microglia, and appearance of peripherally derived monocytes in the CNS.

    “CNS-conditional Tgfb1−/− mice exhibit motor deficits, a loss of homeostatic microglia and the appearance of peripherally derived monocytes in the CNS25.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).This study identifies the molecular and functional signature of homeostatic microglia, which depends on TGFβ signalling. source

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    Premisecitation

    BDNF secreted by microglia causes a shift in the neuronal anion gradient underlying neuropathic pain, and BDNF secretion by microglia is suppressed by IL-1β.

    “BDNF secreted by microglia caused a shift in the neuronal anion gradient underlying neuropathic pain100.”
    • Also stated in: § Trophic support · plain
      “The secretion of BDNF by microglia is suppressed by IL-1β101.”
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    • cites [100] Coull, J. A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005). source

      Not checked in the free run.

    • cites [101] Tong, L. et al. Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1beta via p38 mitogen-activated protein kinase. J. Neurosci. 32, 17714–17724 (2012). source

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    Premisecitation

    CSF1 acting via CSF1R is important for microglial development, and IL-34 promotes tissue-specific signalling required for differentiation of skin myeloid cells and CNS microglia.

    “the cytokine CSF1, acting via its receptor CSF1R, is important for microglial development8.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · boosted
      “interleukin-34 (IL-34), which is an additional ligand for CSF1R, promotes the tissue-specific signalling pathway that is required for the differentiation of myeloid cells that populate the skin and microglia in the CNS68.”
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    • cites [8] Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).References 7 and 8 identify microglia as originating from yolk-sac-derived primitive macrophages. source

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    • cites [68] Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012). source

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    Premisecitation

    SMAD proteins are TGFβ1-dependent and contribute to establishing transcription of specific microglial genes.

    “These include the SMAD proteins, which are TGFβ1-dependent and contribute to establishing transcription of specific microglial genes75.”
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    • cites [75] Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014). source

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    Premisecitation

    SALL1 is expressed in human and mouse microglia, and SALL1 mutations cause neural or behavioural abnormalities in humans and abnormal microglial morphology and homeostatic signature downregulation in mice.

    “Sal-like protein 1 (SALL1), regulates cortical neurogenesis and is expressed in human and mouse microglia25.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “Mutations in SALL1 result in neural or behavioural abnormalities in humans85 and abnormal microglial morphology and downregulation of the microglial homeostatic signature in mice86”
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    • cites [25] Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).This study identifies the molecular and functional signature of homeostatic microglia, which depends on TGFβ signalling. source

      Not checked in the free run.

    • cites [85] Harrison, S. J., Nishinakamura, R., Jones, K. R. & Monaghan, A. P. Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome. Dis. Model. Mech. 5, 351–365 (2012). source

      Not checked in the free run.

    • cites [86] Buttgereit, A. et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17, 1397–1406 (2016). source

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    Premisecitation

    PU.1 is a master regulator of myeloid cells, is crucial for macrophage lineages and microglial genesis, selects microglial enhancers, and binds the CSF1R promoter and most enhancers in mouse and human microglia.

    “The transcription factor PU.1 serves as a master regulator of myeloid cells70. PU.1 plays a crucial role in determining macrophage lineages and microglial genesis and is a major factor in selecting the set of enhancers expressed by microglia.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “PU.1 binds to the CSF1R promoter to drive gene transcription73 and to most enhancers in both mouse and human microglia.”
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    • cites [70] Friedman, A. D. Transcriptional control of granulocyte and monocyte development. Oncogene 26, 6816–6828 (2007). source

      Not checked in the free run.

    • cites [73] Satoh, J., Asahina, N., Kitano, S. & Kino, Y. A. Comprehensive profile of ChIP-Seq-based PU.1/Spi1 target genes in microglia. Gene Regul. Syst. Bio. 8, 127–139 (2014).

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    Premisecitation

    Tonic THIK1 activity promotes microglial ramification and surveillance of the brain parenchyma, and THIK1 is required for IL-1β release by microglia.

    “tonic activity of potassium channel subfamily K member 13 (KCNK13; also known as THIK1) promotes microglial ramification and surveillance of the brain parenchyma69.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “Given that THIK1 is also required for the release of IL-1β by microglia”
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    • cites [69] Madry, C. et al. Microglial ramification, surveillance, and interleukin-1ß release are regulated by the two-pore domain K(+) channel THIK-1. Neuron 97, 299–312 (2018). source

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    Premisecitation

    Microglia secrete neurotrophic factors NGF, BDNF, NT3, FGF, and IGF1 that control receptor tyrosine kinase activity and PI3K signalling, and microglia promote learning-dependent synapse formation via BDNF in mice.

    “Microglia secrete neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), fibroblast growth factor (FGF) and insulin-like growth factor 1 (IGF1), that control the activity of receptor tyrosine kinases and are associated with signalling through phosphoinositide 3-kinase (PI3K)94.”
    • Also stated in: § Trophic support · plain
      “it was shown that microglia promote learning-dependent synapse formation through the secretion of BDNF in mice96.”
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    • cites [94] Shi, S. H., Jan, L. Y. & Jan, Y. N. Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112, 63–75 (2003). source

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    • cites [96] Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013). source

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    Premisecitation

    Inhibition of complement reduces phagocytic microglia and early synapse loss, and C1q is needed for the toxic effects of Aβ oligomers.

    “Inhibition of complement reduces the number of phagocytic microglia as well as the extent of early synapse loss. Furthermore, the complement component C1q is needed for the toxic effects of Aβ oligomers92.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). source

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    Premisecitation

    NRROS-deficient mice lack microglia and are populated by perivascular macrophage-like cells, showing NRROS is important for the programme generating the homeostatic microglial phenotype.

    “Mice deficient in negative regulator of reactive oxygen species (NRROS), which is preferentially expressed in myeloid cells (including macrophages, neutrophils, microglia and perivascular macrophages) and regulates the production of reactive oxygen species, lack microglia and instead are populated by perivascular macrophage-like cells87.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “The lack of microglia in mice lacking NRROS shows that this factor is important for the programme that generates the homeostatic microglial phenotype.”
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    • cites [87] Wong, K. et al. Mice deficient in NRROS show abnormal microglial development and neurological disorders. Nat. Immunol. 18, 633–641 (2017). source

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    Premisecitation

    In macrophages, MAFB promotes an anti-inflammatory phenotype, controls self-renewal, antagonizes GM-CSF, and its expression is downregulated in the SOD1 ALS mouse model.

    “In macrophages, MAFB promotes an anti-inflammatory phenotype, and its loss exacerbates inflammatory conditions80 and controls self-renewal81.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “MAFB also antagonizes granulocyte-macrophage colony-stimulating factor (GM-CSF), which represses microglial differentiation83.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “Furthermore, its expression is downregulated in the superoxide dismutase 1 (SOD1) mouse model of amyotrophic lateral sclerosis (ALS), in which inflammation is increased52,84.”
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    • cites [80] Cuevas, V. D. et al. MAFB determines human macrophage anti-inflammatory polarization: relevance for the pathogenic mechanisms operating in multicentric carpotarsal osteolysis. J. Immunol. 198, 2070–2081 (2017). source

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    • cites [81] Soucie, E. L. et al. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells. Science 351, aad5510 (2016). source

      Not checked in the free run.

    • cites [83] Koshida, R., Oishi, H., Hamada, M. & Takahashi, S. MafB antagonizes phenotypic alteration induced by GM-CSF in microglia. Biochem. Biophys. Res. Commun. 463, 109–115 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Absence of TGFβ1 in the CNS causes a paralytic neurologic disease in mice, and TGFβ1 signalling is inhibited in microglia associated with neurodegeneration where the homeostatic signature is suppressed.

    “the absence of TGFβ1, a factor known to be required for the in vitro development of the molecular signature characteristic of adult microglia, in the CNS results in a paralytic neurologic disease in mice25.”
    • Also stated in: § Mechanisms of homeostatic microglia regulation · plain
      “Importantly, TGFβ1 signalling has also been shown to be inhibited in microglia that are associated with neurodegeneration, in which the homeostatic signature is also suppressed52”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).This study identifies the molecular and functional signature of homeostatic microglia, which depends on TGFβ signalling. source

      Not checked in the free run.

    • cites [52] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).This study identifies a major microglial neurodegenerative phenotype in rodent and humans regulated by TREM2–ApoE signalling. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia from MFP2-deficient mice, which model ageing peroxisomal β-oxidation deficiency, express inflammatory surface markers and downregulate P2RY12 like aged microglia, and Tgfbr1 is downregulated in these mice.

    “Microglia from transgenic mice that lack multifunctional protein 2 (MFP2) and thus model the peroxisomal β-oxidation deficiency common to ageing express inflammatory surface markers and downregulate the homeostatic purinergic receptor P2RY12 (REF.121) in the same manner as aged microglia27.”
    • Also stated in: § Ageing · hedged
      “In MFP2-deficient mice TGFβ receptor 1 (Tgfbr1) is downregulated, suggesting that the loss of homeostatic properties in ageing microglia is also related to the downregulation of this receptor121.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [121] Verheijden, S. et al. Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal beta-oxidation deficiency. Glia 63, 1606–1620 (2015). source

      Not checked in the free run.

    • cites [27] Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reactive gliosis and neural inflammation are hallmarks of AD, and although microglia are not the primary initiator of AD, they play an important cell-autonomous role in the disease.

    “Reactive gliosis and neural inflammation are hallmarks of AD4,122–125.”
    • Also stated in: § Alzheimer disease · plain
      “although not being the primary initiator of AD, microglia play an important cell-autonomous role in the disease.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [4] Sarlus, H. & Heneka, M. T. Microglia in Alzheimer’s disease. J. Clin. Invest. 127, 3240–3249 (2017). source

      Not checked in the free run.

    • cites [122] McGeer, P. L., Itagaki, S., Tago, H. & McGeer, E. G. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci. Lett. 79, 195–200 (1987). source

      Not checked in the free run.

    • cites [123] Griffin, W. S. et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl Acad. Sci. USA 86, 7611–7615 (1989). source

      Not checked in the free run.

    • cites [124] Streit, W. J. Microglia and Alzheimer’s disease pathogenesis. J. Neurosci. Res. 77, 1–8 (2004). source

      Not checked in the free run.

    • cites [125] Streit, W. J., Mrak, R. E. & Griffin, W. S. Microglia and neuroinflammation: a pathological perspective. J. Neuroinflamm. 1, 14 (2004). source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Microglia contribute to neurogenesis through phagocytosis of excessive newborn cells and by promoting neurogenesis through cytokine secretion, and phagocytosis depends on MERTK.

    “Microglia contribute to neurogenesis in two ways: through phagocytosis of excessive newborn cells and by promoting neurogenesis through the secretion of cytokines.”
    • Also stated in: § Neurogenesis · plain
      “Phagocytosis is linked to the homeostatic microglial phenotype and is specifically dependent on the expression of receptor tyrosine kinase MerTK (MERTK), which is responsible for routine non-inflammatory clearance of dead brain cells in the neurogenic niche106.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [105] Sierra, A. et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483–495 (2010). source

      Not checked in the free run.

    • cites [106] Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016).This study shows that microglial MERTK is essential for elimination of apoptotic cells in neurogenic regions of the CNS. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Many microglial changes observed in ALS are also observed in an AD mouse model, suggesting a common microglial response to different disease processes.

    “Many of the microglial changes observed in ALS were also observed in an AD mouse model (see below), suggesting a common microglial response to different disease processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microglia are involved in oligodendrocyte development, and an ITGAX-expressing microglial subset has a key role in myelinogenesis and is a source of IGF1 in the developing brain.

    “It is known that microglia are also involved in oligodendrocyte development. A unique molecular signature of the microglia involved in regulating the development and homeostasis of oligodendrocytes and their progenitors has been identified and shown to be essential for these functions, as confirmed by microglial depletion experiments in mice110.”
    • Also stated in: § Neurogenesis · boosted
      “this ITGAX-expressing microglial subset has been shown to have a key role in myelinogenesis in the developing brain112.”
    • Also stated in: § Neurogenesis · plain
      “an ITGAX-expressing microglial subset was identified as the source of IGF1 in the developing brain112.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Hagemeyer, N. et al. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 134, 441–458 (2017). source

      Not checked in the free run.

    • cites [112] Wlodarczyk, A. et al. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 36, 3292–3308 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia attract monocytes to the brain in a CCL2-dependent fashion, and these monocytes do not contribute to the resident microglial pool.

    “Microglia attract monocytes to the brain in a CC-chemokine ligand 2 (CCL2)-dependent fashion. These monocytes play an important role in neuroinflammation but do not contribute to the resident microglial pool102.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).Using a parabiosis paradigm, this study shows that recruited monocytes do not contribute to the resident microglial pool. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the SOD1 ALS mouse, Tau, presenilin 2, and ApoE pathways are activated in microglia, Apoe is among the most induced transcripts during progression, and loss of the homeostatic microglial signature occurs as early as 2 months before measurable disease onset.

    “Tau, presenilin 2 and apolipoprotein E (ApoE) pathways were found to be activated in microglia in the SOD1 mouse, with Apoe being one of the transcripts that was the most significantly induced during disease progression.”
    • Also stated in: § Amyotrophic lateral sclerosis · plain
      “this study also revealed loss of the homeostatic microglial signature described above as early as 2 months before measurable disease onset in the SOD1 mouse.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013). source

      Not checked in the free run.

    • cites [84] Butovsky, O. et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015).This study validates miR-155 as a therapeutic target to modulate microglia in a mouse model and in human ALS. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recruitment of CCR2-expressing monocytes is important in mouse models of AD, where CCR2 deletion impairs monocyte accumulation and accelerates disease progression.

    “The recruitment of CCR2-expressing monocytes also plays an important role in mouse models of AD, in which genetic deletion of CCR2 in mice impairs monocyte accumulation and accelerates disease progression103.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia activated by IL-4 or IFNγ induce oligodendrogenesis or neurogenesis from adult stem cell progenitors, and high but not low IFNγ impedes oligodendrogenesis, which IL-4 reduces.

    “Microglia activated by IL-4 or IFNγ induced oligodendrogenesis or neurogenesis, respectively, from adult stem cell progenitor cells both in vivo and in vitro113. High, but not low, levels of IFNγ induced a microglial phenotype that impeded oligodendrogenesis. IL-4 reduced this impediment and overcame the blockage of IGF1 production that was caused by IFNγ113.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Butovsky, O. et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosciences 31, 149–160 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During many diseases, microglia lose their homeostatic molecular signature and functions, such as synaptic plasticity, and become chronically inflammatory.

    “during the course of many diseases, microglia lose their homeostatic molecular signature and functions26,84,114, such as their roles in synaptic plasticity115, and become chronically inflammatory116.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [26] Holtman, I. R. et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol. Commun. 3, 31 (2015). source

      Not checked in the free run.

    • cites [84] Butovsky, O. et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015).This study validates miR-155 as a therapeutic target to modulate microglia in a mouse model and in human ALS. source

      Not checked in the free run.

    • cites [114] Moore, C. S. et al. P2Y12 expression and function in alternatively activated human microglia. Neurol. Neuroimmunol. Neuroinflamm. 2, e80 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged microglia display a dystrophic phenotype, ageing induces a hypersensitive pro-inflammatory primed phenotype, sensome genes are downregulated, and aged microglia express LGALS3, AXL, CLEC7A, MHC class II, and CXCR4 while appearing activated but not polarized.

    “Aged microglia display a dystrophic phenotype118–120. It is also known that ageing, similar to neurodegeneration, induces a hypersensitive, pro-inflammatory microglial phenotype that some have referred to as ‘primed microglia’26.”
    • Also stated in: § Ageing · plain
      “In ageing mice, most of the ‘sensome’ genes (which encode proteins involved in sensing endogenous ligands and microorganisms) that are expressed by homeostatic microglia are downregulated27.”
    • Also stated in: § Ageing · hedged
      “These cells also express pro-inflammatory cell surface markers such as galectin 3 (LGALS3), tyrosine-protein kinase receptor UFO (AXL), CLEC7A, major histocompatibility complex (MHC) class II molecules and CXC-chemokine receptor 4 (CXCR4)26 and appear immunologically activated but not polarized to a pro- or anti-inflammatory phenotype25.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [118] Streit, W. J., Sammons, N. W., Kuhns, A. J. & Sparks, D. L. Dystrophic microglia in the aging human brain. Glia 45, 208–212 (2004). source

      Not checked in the free run.

    • cites [119] Streit, W. J. Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosciences 29, 506–510 (2006).References 118 and 119 propose that microglial senescence is important for age-related decline in cognitive function. source

      Not checked in the free run.

    • cites [120] Flanary, B. E., Sammons, N. W., Nguyen, C., Walker, D. & Streit, W. J. Evidence that aging and amyloid promote microglial cell senescence. Rejuven. Res. 10, 61–74 (2007). source

      Not checked in the free run.

    • cites [26] Holtman, I. R. et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol. Commun. 3, 31 (2015). source

      Not checked in the free run.

    • cites [27] Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus.

    “It has also been shown that infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus104.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Varvel, N. H. et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc. Natl Acad. Sci. USA 113, E5665–E5674 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial expression of complement receptor CR1 has been linked to late-onset AD and may reflect microglial phagocytosis of synapses proposed to contribute to AD pathogenesis.

    “microglial expression of the complement receptor CR1 has been linked to late-onset AD137,138 and may reflect the microglial phagocytosis of synapses that has been proposed to contribute to AD pathogenesis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [137] Thambisetty, M. et al. Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. Biol. Psychiatry 73, 422–428 (2013). source

      Not checked in the free run.

    • cites [138] Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, peripheral monocytes can enter the brain, clear Aβ and affect disease pathology, and this effect is lost in Ccr2−/− animals.

    “For example, in mice, peripheral monocytes can enter the brain, clear Aβ and affect disease pathology144, an effect that is lost in Ccr2−/− animals103.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [144] Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49, 489–502 (2006). source

      Not checked in the free run.

    • cites [103] El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Microglial neurotoxicity may be related to their expression of tau, which is triggered by Aβ deposition and is neurotoxic.

    “The neurotoxicity of microglial cells may also be related to their expression of tau, which is triggered by the deposition of Aβ in the brain and is known to be neurotoxic149.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405 (2015). source

      Not checked in the free run.

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

    Interpretationnone given

    Multiple microglial phenotypes are likely associated with disease, and DAM microglia as defined may have either beneficial or detrimental functions.

    “It is important to note that there are likely to be multiple microglial phenotypes associated with disease and that DAM microglia as defined may have either beneficial or detrimental function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    With Aβ deposition, microglial cells become more neurotoxic and express inflammatory cytokines including IL-1β, IL-6, TNF and CCL3.

    “Furthermore, with the deposition of Aβ, the phenotype of microglial cells becomes more neurotoxic118,146–148: they express several inflammatory cytokines, including IL-1β, IL-6, tumour necrosis factor (TNF) and CCL3 (also known as MIP1α)146.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [118] Streit, W. J., Sammons, N. W., Kuhns, A. J. & Sparks, D. L. Dystrophic microglia in the aging human brain. Glia 45, 208–212 (2004). source

      Not checked in the free run.

    • cites [146] Sastre, M., Klockgether, T. & Heneka, M. T. Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int. J. Dev. Neurosci. 24, 167–176 (2006). source

      Not checked in the free run.

    • cites [147] Perry, V. H., Cunningham, C. & Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167 (2007). source

      Not checked in the free run.

    • cites [148] Rojo, L. E., Fernandez, J. A., Maccioni, A. A., Jimenez, J. M. & Maccioni, R. B. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch. Med. Res. 39, 1–16 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human multiple sclerosis, microglia lose P2RY12 expression and adopt a pro-inflammatory phenotype with phagocytic markers, antigen presentation markers and reactive oxygen species production proteins.

    “In human MS, microglia lose the expression of the P2RY12 homeostatic microglial marker and adopt a pro-inflammatory phenotype that includes the expression of phagocytic-related markers (macrosialin (also known as CD68)), antigen presentation markers (MHC class I and II molecules and T lymphocyte activation antigen CD86) and proteins involved in the production of reactive oxygen species (cytochrome”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Zrzavy, T. et al. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 140, 1900–1913 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Over time, microglia may become activated, and this change is linked to peripheral signals that occur with ageing or disease.

    “Independent of the specific disease, it appears that, over time, microglia may transform into an activated state and that this change is related to signals from the periphery that occur with ageing or disease143.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Hoeijmakers, L., Heinen, Y., van Dam, A. M., Lucassen, P. J. & Korosi, A. Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics? Front. Hum. Neurosci. 10, 398 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DAM microglia arise through two activation steps: homeostatic microglia first become stage 1 DAM independently of TREM2, then become stage 2 DAM dependently on TREM2.

    “These DAM microglia were shown to be generated through a two-step activation process in which homeostatic microglia first transition to an intermediate stage (known as stage 1 DAM) in a TREM2-independent manner, followed by a second TREM2-dependent transition to stage 2 DAM111.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).This study utilizes unbiased single-cell RNA-sequencing analysis to define DAM microglia. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DAM microglia have been found in ageing, ALS, frontotemporal dementia and an inducible CK-p25 mouse model of severe neurodegeneration.

    “DAM microglia have been observed in other conditions including ageing, ALS and frontotemporal dementia (FTD) and in an inducible CK-p25 mouse model of severe neurodegeneration”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).This study utilizes unbiased single-cell RNA-sequencing analysis to define DAM microglia. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia are the only brain cells that express CX3CR1, which has an immunomodulatory role in homeostasis, and its genetic ablation causes neurotoxicity.

    “Microglia are the only cells in the brain to express CX3CR1, which serves an immunomodulatory role in the homeostatic state and the genetic ablation of which results in neurotoxicity78.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917–924 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Microglia undergo cellular reprogramming in response to neurodegeneration, and this process involves distinct transcriptional programmes.

    “These studies emphasize that cellular reprogramming of microglia occurs in response to neurodegeneration and that this process is related to unique underlying transcriptional programmes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TREM2 affects microglial metabolic fitness; Alzheimer disease patients with TREM2 risk variants and TREM2-deficient mice have abundant autophagic vesicles in their microglia.

    “Consistent with this, it was found that TREM2 also affects microglial metabolic fitness: patients with AD carrying TREM2 risk variants and TREM2-deficient mice have abundant autophagic vesicles in their microglia178.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury in mice.

    “Consistent with this, TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury in mice168.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Mazaheri, F. et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 18, 1186–1198 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking CX3CR1 show a transient reduction in brain microglia during the early postnatal period and a later deficit in synaptic pruning associated with impaired social behaviour.

    “Consistent with this, mice lacking CX3CR1 exhibit a transient reduction in the numbers of microglia present in the brain during the early postnatal period and a subsequent deficit in synaptic pruning associated with impaired social behaviour164.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated microglia are prominent in mouse models and in human Parkinson disease.

    “Although molecular profiling of microglia in animal models of PD has yet to be attempted, activated microglia are known to be prominent in mouse models and in human PD160.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Joers, V., Tansey, M. G., Mulas, G. & Carta, A. R. Microglial phenotypes in Parkinson’s disease and animal models of the disease. Prog. Neurobiol. 155, 57–75 (2017). source

      Not checked in the free run.

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

    Interpretationcitation

    α-Synuclein-dependent activation of microglia may be linked to changes in the microbiome in animal models and patients.

    “it has been reported that α-synuclein-dependent activation of microglia may be linked to changes in the microbiome in both animal models and patients162.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016). source

      Not checked in the free run.

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

    Premisecitation

    TREM2 promotes microglial survival by activating the WNT-β-catenin signalling pathway.

    “It has been reported that TREM2 promotes microglial survival by activating the WNT-β-catenin signalling pathway167.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Zheng, H. et al. TREM2 Promotes Microglial Survival by Activating Wnt/beta-Catenin Pathway. J. Neurosci. 37, 1772–1784 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    Trem2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer disease mouse models.

    “However, others have reported that Trem2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in AD mouse models173, which is seemingly inconsistent with the link between TREM2 loss-of-function mutations and an increased risk of AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ApoE binds to apoptotic neurons and increases TREM2-mediated microglial phagocytosis of neurons.

    “It binds to apoptotic neurons and increases TREM2-mediated microglial phagocytosis of neurons179.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Atagi, Y. et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043–26050 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In EAE, TREM2 is upregulated in spinal cord microglia and an anti-TREM2 antibody exacerbates disease.

    “Indeed, in EAE it has been shown that TREM2 is upregulated in spinal cord microglia and that an anti-TREM2 antibody exacerbates disease172.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [172] Piccio, L. et al. Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur. J. Immunol. 37, 1290–1301 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Minocycline specifically affects microglia, a trial in multiple sclerosis showed positive trends, and minocycline worsened patients with ALS.

    “Minocycline has been shown to specifically affect microglia153–155, and a trial in MS showed positive trends156, although minocycline worsened patients with ALS157.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [153] Kobayashi, K. et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 4, e525 (2013). source

      Not checked in the free run.

    • cites [154] Sriram, K., Miller, D. B. & O’Callaghan, J. P. Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J. Neurochem. 96, 706–718 (2006). source

      Not checked in the free run.

    • cites [155] Ledeboer, A. et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115, 71–83 (2005). source

      Not checked in the free run.

    • cites [156] Metz, L. M. & Eliasziw, M. Trial of minocycline in clinically isolated syndrome of multiple sclerosis. N. Engl. J. Med. 377, 789 (2017). source

      Not checked in the free run.

    • cites [157] Gordon, P. H. et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 6, 1045–1053 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phagocytosis of apoptotic neurons injected into naive mouse brain suppressed the microglial homeostatic signature and produced a transcriptional profile mimicking MGnD microglia.

    “Phagocytosis of apoptotic neurons that were injected into the brain of naive mice suppressed the microglial homeostatic signature and resulted in a transcriptional profile that mimicked the molecular signature of MGnD microglia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).This study identifies a major microglial neurodegenerative phenotype in rodent and humans regulated by TREM2–ApoE signalling. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ-induced microglial activation is impaired in humanized transgenic mice expressing human R47H TREM2, and the R47H mutation impairs TREM2 binding to anionic lipids.

    “Aβ-induced microglial activation is impaired in humanized transgenic mice expressing human R47H TREM2 (REF.169), and the R47H mutation impairs TREM2 binding to anionic lipids166.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [169] Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018). source

      Not checked in the free run.

    • cites [166] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).This study demonstrates that microglial TREM2 is a sensor for lipids associated with fibrillar Aβ and its loss affects microglia and augments Aβ accumulation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the absence of TREM2, microglia do not fully surround Aβ plaques, and Aβ plaques are more diffuse and associated with greater neuritic damage.

    “In the absence of TREM2, it has been reported that microglia do not fully surround Aβ plaques and that Aβ plaques are more diffuse and associated with greater neuritic damage174.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [174] Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trem2 deficiency ameliorates amyloid pathology at early stages but exacerbates it at late stages, suggesting TREM2 has distinct roles at different disease stages.

    “Trem2 deficiency ameliorated amyloid pathology at early stages but exacerbated it at late stages, suggesting that TREM2 plays distinct roles at different stages of disease175.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [175] Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017).References 173–175 show time-dependent differential effects of TREM2-dependent microglial function in AD mouse models. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 recognizes phosphatidylserine on apoptotic or damaged cells and initiates ApoE signalling.

    “Although it is not entirely clear how TREM2 regulates microglial signature phenotypes, TREM2 is known to recognize phosphatidylserine on the surface of apoptotic or damaged cells and to initiate ApoE signalling52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).This study identifies a major microglial neurodegenerative phenotype in rodent and humans regulated by TREM2–ApoE signalling. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 detects damage-associated lipids, allowing microglia to sense Aβ accumulation, and its loss augments Aβ accumulation in a mouse model of Alzheimer disease.

    “TREM2 is a receptor that detects damage-associated lipids, allowing microglia to sense Aβ accumulation, and its loss has been shown to augment Aβ accumulation in a mouse model of AD166.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).This study demonstrates that microglial TREM2 is a sensor for lipids associated with fibrillar Aβ and its loss affects microglia and augments Aβ accumulation. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    TREM2 protects against Alzheimer disease by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.

    “These findings are consistent with the interpretation that TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Microglia are damage sensors of the CNS and act as phagocytes for routine, non-inflammatory clearance of dead brain cells.

    “As discussed above, microglia are damage sensors of the CNS and act as phagocytes for the routine, non-inflammatory clearance of dead brain cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the tau model of neurodegeneration, genetic deletion of either Apoe or Trem2 arrested neurodegeneration, demonstrating that this pathway negatively regulates the homeostatic signature.

    “In the tau model of neurodegeneration, genetic deletion of either Apoe or Trem2 also arrested neurodegeneration, demonstrating that this pathway negatively regulates the homeostatic signature182,183.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [182] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). source

      Not checked in the free run.

    • cites [183] Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017).References 182 and 183 connect TREM2 and ApoE signalling with exacerbation of neuroinflammation and tauopathy. source

      Not checked in the free run.

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

    Interpretationnone given

    Microglia have been redefined as having either a homeostatic or a disease-associated phenotype based on molecular signature, and many pathways regulating these signatures have been elucidated.

    “As described in this article, microglia have now been redefined as having either a homeostatic or a disease-associated phenotype on the basis of their molecular signature, and many of the pathways that regulate these signatures have been elucidated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Microglial expression of Axl is upregulated and Mer is downregulated in MGnD microglia.

    “Microglial expression of Axl is upregulated and Mer is downregulated in microglia exhibiting the MGnD phenotype52.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).This study identifies a major microglial neurodegenerative phenotype in rodent and humans regulated by TREM2–ApoE signalling. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GW2580 inhibited CSF1R in the APP/PS1 mouse model of Alzheimer disease, reducing microglial proliferation and the microglial inflammatory profile.

    “Similarly, an oral tyrosine kinase inhibitor (GW2580) inhibited CSF1R in the APP/PS1 mouse model of AD, which reduced microglial proliferation and the microglial inflammatory profile190.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891–907 (2016). source

      Not checked in the free run.

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

    Interpretationnone given

    Other biomarkers to measure microglial function could be present in cerebrospinal fluid.

    “Other biomarkers to measure microglial function could be present in the cerebrospinal fluid.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PLX3397 treatment reduced accumulation of intraneuronal Aβ, neuritic plaque deposition and pre-fibrillar oligomers in the same Alzheimer disease mouse model.

    “In addition, PLX3397 treatment was reported to reduce accumulation of intraneuronal Aβ, neuritic plaque deposition and pre-fibrillar oligomers in the same mouse model of AD186.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Sosna, J. et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease. Mol. Neurodegener. 13, 11 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Methods to image microglia exist and are being used to test treatment effects on microglia.

    “Methods to image microglia exist and are being used to test the effect of treatments on microglia205–210.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [205] Nimmerjahn, A. Two-photon imaging of microglia in the mouse cortex in vivo. Cold Spring Harb. Protoc. https://doi.org/10.1101/pdb.prot069294 (2012). source

      Not checked in the free run.

    • cites [206] Dupont, A. C. et al. Translocator protein-18 kDa (TSPO) positron emission tomography (PET) imaging and its clinical impact in neurodegenerative diseases. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18040785 (2017). source

      Not checked in the free run.

    • cites [207] Ghadery, C. et al. Microglial activation in Parkinson’s disease using [18F]-FEPPA. J. Neuroinflamm. 14, 8 (2017). source

      Not checked in the free run.

    • cites [208] Cerami, C., Iaccarino, L. & Perani, D. Molecular imaging of neuroinflammation in neurodegenerative dementias: the role of in vivo PET imaging. Int. J. Mol. Sci. FF (2017). source

      Not checked in the free run.

    • cites [209] Hamelin, L. et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139, 1252–1264 (2016). source

      Not checked in the free run.

    • cites [210] Politis, M., Su, P. & Piccini, P. Imaging of microglia in patients with neurodegenerative disorders. Front. Pharmacol. 3, 96 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological targeting of CSF1R improved cognition and prevented synaptic degeneration in the APP/PS1 model.

    “Pharmacological targeting of CSF1R in this study also improved cognition and prevented synaptic degeneration190.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891–907 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with PLX5622 prevented association of microglia with plaques and improved cognition in the 3xTg-AD mouse model of Alzheimer disease.

    “Treatment with PLX5622, which also targets CSF1R, prevented the association of microglia with plaques and improved cognition in the 3xTg-AD mouse model of AD189.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Dagher, N. N. et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J. Neuroinflamm. 12, 139 (2015). source

      Not checked in the free run.

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

    Premisenone given

    Microglia are resident cells of the nervous system that are independent from myeloid cells migrating into the brain from the periphery.

    “As outlined above, it is now recognized that microglia are resident cells of the nervous system that are independent from myeloid cells that migrate into the brain from the periphery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ablation of microglia by PLX3397, a CSF1R inhibitor, did not reduce plaque burden but did protect synapses.

    “Consistent with a potential detrimental role of microglia, it was shown that ablation of microglia by a compound (PLX3397) that inhibits CSF1R did not reduce plaque burden, although it did protect synapses185.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some anti-inflammatory drugs diminish neuroinflammation, but few have direct functional effects on microglial activity.

    “However, although some anti-inflammatory drugs have been shown to diminish neuroinflammation, few have direct functional effects on microglial activity192.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Lleo, A., Galea, E. & Sastre, M. Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases. Cell. Mol. Life Sci. 64, 1403–1418 (2007). source

      Not checked in the free run.

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

    Interpretationreasoning

    These treatments would be expected to mediate their effects by modulating the microglial homeostatic signature.

    “On the basis of our current understanding of microglial physiology, these treatments would be expected to mediate their effects by modulating the microglial homeostatic signature.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Germ-free animals or mice treated with broad-spectrum antibiotics develop dysfunctional microglia, an effect ameliorated by short-chain fatty acids.

    “Animals raised in a germ-free environment or mice treated with broad-spectrum antibiotics develop dysfunctional microglia, an effect that can be ameliorated with short-chain fatty acids.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [199] Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    TAM receptors may control microglial physiology and are potential targets for therapeutic intervention.

    “Thus, TAM receptors may control microglial physiology and are potential targets for therapeutic intervention.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The distinction between homeostatic and disease-associated signatures is not absolute, particularly in terms of impact on disease; some non-homeostatic disease signatures may have beneficial roles in halting disease, as illustrated by paradoxical TREM2 findings.

    “Nonetheless, the distinction between homeostatic and disease-associated signatures is not absolute, particularly in terms of their impact on disease: some microglial disease signatures that are not homeostatic may in fact have beneficial roles in halting the disease process, as illustrated by the paradoxical findings with TREM2.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    MERTK on microglia is required for clearing apoptotic cells in the neurogenic regions of the CNS.

    “This study shows that microglial MERTK is essential for elimination of apoptotic cells in neurogenic regions of the CNS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016).This study shows that microglial MERTK is essential for elimination of apoptotic cells in neurogenic regions of the CNS. source

      Not checked in the free run.

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

    Premisecitation

    Only transplanted macrophages of yolk sac origin achieve full microglial identity.

    “This study shows that transplanted macrophages from multiple tissues can express microglial genes in the brain; however, only those of yolk sac origin fully attain microglial identity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [220] Bennett, F. C. et al. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183 (2018).This study shows that transplanted macrophages from multiple tissues can express microglial genes in the brain; however, only those of yolk sac origin fully attain microglial identity. source

      Not checked in the free run.

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

    Premisecitation

    Microglia repopulate rapidly after being depleted pharmacologically.

    “This report shows rapid repopulation of microglia following pharmacological depletion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014).This report shows rapid repopulation of microglia following pharmacological depletion. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TREM2 and ApoE signalling are linked to worsened neuroinflammation and tauopathy.

    “References 182 and 183 connect TREM2 and ApoE signalling with exacerbation of neuroinflammation and tauopathy.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [182] Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). source

      Not checked in the free run.

    • cites [183] Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017).References 182 and 183 connect TREM2 and ApoE signalling with exacerbation of neuroinflammation and tauopathy. source

      Not checked in the free run.

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

    Premisecitation

    Disrupting the PU.1 gene alters myeloid development and several haematopoietic processes that are developmentally regulated.

    “This study demonstrates that PU.1 gene disruption affects a number of developmentally regulated haematopoietic processes and myeloid development.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Anderson, K. L. et al. Myeloid development is selectively disrupted in PU.1 null mice. Blood 91, 3702–3710 (1998).This study demonstrates that PU.1 gene disruption affects a number of developmentally regulated haematopoietic processes and myeloid development. source

      Not checked in the free run.

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

    Premisecitation

    Toxic astrocytes of this kind contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders.

    “This study shows that classically activated neuroinflammatory microglia induce toxic astrocytes, which contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).This study shows that classically activated neuroinflammatory microglia induce toxic astrocytes, which contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders. source

      Not checked in the free run.

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

    Premisecitation

    Microglia activated along the classical neuroinflammatory pathway cause astrocytes to become toxic.

    “This study shows that classically activated neuroinflammatory microglia induce toxic astrocytes, which contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).This study shows that classically activated neuroinflammatory microglia induce toxic astrocytes, which contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders. source

      Not checked in the free run.

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

    Premisecitation

    Microglial senescence plays an important part in the cognitive decline that accompanies ageing.

    “References 118 and 119 propose that microglial senescence is important for age-related decline in cognitive function.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [118] Streit, W. J., Sammons, N. W., Kuhns, A. J. & Sparks, D. L. Dystrophic microglia in the aging human brain. Glia 45, 208–212 (2004). source

      Not checked in the free run.

    • cites [119] Streit, W. J. Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosciences 29, 506–510 (2006).References 118 and 119 propose that microglial senescence is important for age-related decline in cognitive function. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Losing TREM2 alters microglia and increases the accumulation of Aβ.

    “This study demonstrates that microglial TREM2 is a sensor for lipids associated with fibrillar Aβ and its loss affects microglia and augments Aβ accumulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).This study demonstrates that microglial TREM2 is a sensor for lipids associated with fibrillar Aβ and its loss affects microglia and augments Aβ accumulation. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The microglial signatures identified to date provide a basis to identify new therapeutic targets and to measure effects of microglial-directed therapies.

    “The microglial signatures that have been identified to date will provide a basis to identify new therapeutic targets and to measure the effect of microglial-directed therapies.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Distinct regulatory circuits control the transcriptome profiles and the temporal stages of development of early, pre-adult microglia.

    “This study uses single-cell RNA-sequencing and bioinformatics to describe microglial transcriptome profiles and temporal stages of development in early, pre-adult microglia, which are regulated by distinct regulatory circuits.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).This study uses single-cell RNA-sequencing and bioinformatics to describe microglial transcriptome profiles and temporal stages of development in early, pre-adult microglia, which are regulated by distinct regulatory circuits. source

      Not checked in the free run.

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

    Premisecitation

    Macrophages transplanted from various tissues are able to express microglial genes in the brain.

    “This study shows that transplanted macrophages from multiple tissues can express microglial genes in the brain; however, only those of yolk sac origin fully attain microglial identity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [220] Bennett, F. C. et al. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183 (2018).This study shows that transplanted macrophages from multiple tissues can express microglial genes in the brain; however, only those of yolk sac origin fully attain microglial identity. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia display transcriptional heterogeneity that depends on age and on brain region.

    “This study describes the age-dependent and region-dependent transcriptional heterogeneity of microglia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).This study describes the age-dependent and region-dependent transcriptional heterogeneity of microglia. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Innate immunity contributes to Alzheimer disease through altered PU.1-driven transcriptional regulation in microglia and blood monocytes.

    “This study implicates innate immunity in AD through alteration of PU.1 core transcriptional regulation of microglia and blood monocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Huang, K. L. et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat. Neurosci. 20, 1052–1061 (2017).This study implicates innate immunity in AD through alteration of PU.1 core transcriptional regulation of microglia and blood monocytes. source

      Not checked in the free run.

95 of 95

  • The paper relies on this without support.

    A common neurodegenerative microglial signature exists for diseases such as ALS, AD, and MS.

    “At the present time, a common neurodegenerative microglial signature has been identified for diseases such as ALS, AD and MS.”

  • The paper relies on this without support.

    Innate immune cells can protect against Alzheimer disease by reducing Aβ accumulation during early stages of disease.

    “It is known that innate immune cells can protect against AD by reducing the accumulation of Aβ, which occurs during early stages of disease.”
2 of 2

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?

  • Under normal conditions, microglia help maintain homeostasis by providing neurotrophic support and clearing harmful substances, such as amyloid plaques, through phagocytosis.

    “Under normal conditions, they help maintain homeostasis by providing neurotrophic support and clearing harmful substances, such as amyloid plaques, through phagocytosis [8, 9, 10].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [8]

    The Trophic support section says microglia secrete neurotrophic factors, and the Neurogenesis section describes homeostatic clearance of dead cells by phagocytosis. The Alzheimer disease section discusses possible microglial phagocytosis of Aβ, but does not establish amyloid-plaque clearance as a normal homeostatic function; it says the role of plaque-associated microglia remains uncertain. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • By orchestrating gene expression, transcription factors influence whether microglia play protective or detrimental roles in maintaining brain homeostasis and responding to disease.

    “By orchestrating gene expression, transcription factors influence whether microglia play protective or detrimental roles in maintaining brain homeostasis and responding to disease [8, 13].”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [8]

  • Microglial activation is facilitated by intrinsic and extrinsic factors, leading to precise reprogramming of the microglial phenotype.

    “It is well established that microglial activation is facilitated by both intrinsic and extrinsic factors, leading to precise reprogramming of the microglial phenotype [58,59].”

    From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [58]

  • Microglia display diverse and dynamic phenotypic states and play roles in development, adulthood, aging, and diseases.

    “Microglia display diverse and dynamic phenotypic states and play a plethora of roles in development, adulthood (homeostasis), aging and diseases (Butovsky and Weiner, 2018; Prinz et al., 2019; Thion and Garel, 2020).”

    From What is a cell type and how to define it? (2022) · cites this paper as Butovsky and Weiner, 2018

  • Igf1 is abundantly expressed by microglia during postnatal development, aging, or following brain injuries and plays a vital role in promoting neuronal survival.

    “Igf1 is abundantly expressed by microglia during postnatal development, aging or following brain injuries and plays a vital role in promoting neuronal survival (59,63–66).”

    From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [59]

Cites

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1 of the 225 references couldn’t be matched to a known paper.

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Related

Authors
Butovsky, O., & Weiner, H. L.
Affiliations
Brigham and Women's Hospital (US)
Corresponding author
  • Butovsky, Oleg
  • Weiner, Howard L.
ORCID
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2018-09-11
Volume
19
Issue
10
Pages
622-635
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/s41583-018-0057-5
PMC
PMC7255106
OpenAlex
W2890187093
Semantic Scholar
06b85485b0376c63afcb4391ad2551d9a4da8702
Cited by
1,046
References
225
Citations by year
2026: 103 · 2025: 143 · 2024: 191 · 2023: 146 · 2022: 153 · 2021: 158 · 2020: 90 · 2019: 53 · 2018: 7 · 2012: 1
FWCI
7.28
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG043975, R01AG040092, R01AG051812, R01AG054672)
  • National Eye Institute (R01EY027921)
  • National Institute of Neurological Disorders and Stroke (R21NS104609, R21NS101673, R01NS088137, R01NS136122)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
microglia, homeostatic microglia, disease-associated microglia, gene expression profiling, surface protein expression, microglial plasticity, neuroinflammation
MeSH terms
Animals, Central Nervous System, Homeostasis, Humans, Membrane Proteins, Microglia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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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