CoChat
Sign Up
Cited by 2,894Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsNeurogenesis and neuroplasticity mechanisms

The DOI matches its Crossref record; 205 of the 205 references it cites were found in a registry or an index; none of the 147 sources its claims cite is checked for support yet.

Microglia Function in the Central Nervous System During Health and Neurodegeneration

Open access
Colonna, Marco, Butovsky, Oleg·2017·Annual Review of Immunology
DOI 10.1146/annurev-immunol-051116-052358PMC PMC8167938
Open this paper in CoChat — free accountOpen PDF

Abstract

Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration. Recent observations about microglia ontogeny combined with extensive gene expression profiling and novel tools to study microglia biology have allowed us to characterize the spectrum of microglial phenotypes during development, homeostasis, and disease. In this article, we review recent advances in our understanding of the biology of microglia, their contribution to homeostasis, and their involvement in neurodegeneration. Moreover, we highlight the complexity of targeting microglia for therapeutic intervention in neurodegenerative diseases.

Overview

Integrity signals

Registry

Crossref · 10.1146/annurev-immunol-051116-052358

Cites

205 of 205 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 147 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Microglia development and maintenance depend on constant engagement of CSF1R, which transmits intracellular signals such as AKT and ERK that promote microglia proliferation and survival.

    “Microglia development and maintenance depend on constant engagement of colony stimulating factor 1 receptor (CSF1R), a receptor tyrosine kinase that transmits intracellular signals, such as activation of protein kinase B (also known as AKT) and extracellular signal-regulated kinases (ERK), that promote microglia proliferation and survival (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] source
  • Premisecitation

    Bone marrow-derived myeloid precursors do not contribute to the microglia pool.

    “Bone marrow–derived myeloid precursors do not contribute to the microglia pool.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] source
    • cites [2] source
  • Premisenone given

    Microglia express many pattern-recognition receptors that detect pathogen-associated molecular patterns or tissue damage-associated molecular patterns.

    “Microglia express many pattern-recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) or tissue damage–associated molecular patterns (DAMPs).”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Microglia eliminate microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS.

    “They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Transcriptome studies show that microglia activation is varied and context dependent.

    “In fact, transcriptome studies show that microglia activation is varied and context dependent.”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 56
  • Probably not a substantial claim. 2

  • It may state two separate claims as one.

    Premisecitation

    In the steady state, microglia are ramified cells with multiple branches and processes that are in continuous motion, protruding and retracting to survey large areas of the brain.

    “In the steady state, microglia are ramified cells with multiple branches and processes, which extend from the somata and terminate with bulbous endings. These processes are in continuous motion, protruding and retracting to cover long distances and survey large areas of the brain.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] source
    • cites [13] source
    • cites [14] source

  • It may state two separate claims as one.

    Premisereasoning

    Larger injuries or inflammatory stimuli induce microglia to morph from a ramified to an amoeboid shape, which reflects a highly activated state associated with phagocytosis and proinflammatory function.

    “Larger injuries or inflammatory stimuli induce microglia to morph from a ramified to an amoeboid shape. Cell bodies enlarge while cell processes become shortened and cover more limited areas. Amoeboid morphology reflects a highly activated state associated with phagocytosis and proinflammatory function.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisenone given

    Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration.

    “Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Microglia originate from early myeloid progenitors in the embryonic yolk sac that migrate into the developing neural tube, proliferate, colonize the entire parenchyma, and persist throughout life by slow division.

    “Fate-mapping studies have demonstrated that microglia originate from early myeloid progenitors in the embryonic yolk sac that migrate into the developing neural tube, where they proliferate, colonize the entire parenchyma, and subsist throughout the life span of the organism by slow division (1, 2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] source
    • cites [2] source

  • It may state two separate claims as one.

    Interpretationnone given

    Microglia act as brain macrophages but differ from other tissue macrophages because of a unique homeostatic phenotype and tight regulation by the CNS microenvironment.

    “Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationnone given

    Microglia are resident brain cells that regulate brain development, maintenance of neuronal networks, and injury repair.

    “Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Genetic defects in CSF1R and pharmacological blockade of CSF1R drastically reduce microglia numbers.

    “Genetic defects in CSF1R and pharmacological blockade of CSF1R drastically reduce microglia numbers (5, 6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] source
    • cites [6] source

  • It may state two separate claims as one.

    Premisenone given

    Microglia are the primary source of proinflammatory cytokines and pivotal mediators of neuroinflammation, capable of inducing or modulating a broad spectrum of cellular responses.

    “Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    IL-34 and CSF1 are partially redundant, such that genetic defects in either result in a partial reduction of microglial numbers.

    “Thus, IL-34 and CSF1 are partially redundant, such that genetic defects in either IL-34 or CSF1 result in a partial reduction of microglial numbers.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Microglia express multiple receptors for neurotransmitters and neuropeptides released by neurons that promote neural-glia communications and allow microglia to monitor neuronal activity and influence synaptic plasticity.

    “In addition to immune receptors, microglia express multiple receptors for neurotransmitters and neuropeptides released by neurons that promote neural-glia communications (31). These receptors allow microglia to monitor neuronal activity by guiding microglia processes toward neuronal synapses in order to influence synaptic plasticity and sculpt dendritic spine density.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] source

  • It may state two separate claims as one.

    Premisecitation

    In models of neurodegeneration, microglia express both neurotoxic and neuroprotective factors, as well as genes involved in oxidative phosphorylation and lysosome, ribosome, and spliceosome factors involved in responses to misfolded proteins, stress, and neuronal death or injury.

    “In models of neurodegeneration, microglia express both neurotoxic and neuroprotective factors; genes involved in oxidative phosphorylation; and lysosome, ribosome, and spliceosome factors involved in responses to misfolded proteins, stress, and neuronal death or injury (36, 42) (Figure 1).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] source
    • cites [42] source

  • It may state two separate claims as one.

    Premisecitation

    M1 activation is a proinflammatory and neurotoxic state, whereas M2 activation describes anti-inflammatory and healing activities of microglia.

    “M1 activation is a proinflammatory and neurotoxic state typically induced by simultaneous triggering of TLR and IFN-γ signaling pathways.”
    • Also stated in: § Functional States of Microglia: Beyond the M1/M2 Paradigm · plain
      “M2 activation describes the anti-inflammatory and healing activities of microglia.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Appel SH, 2011, Acta Myol
    • cites [35] source

  • It may state two separate claims as one.

    Interpretationreasoning

    The M1/M2 paradigm is increasingly considered inadequate to describe microglia and macrophage activation in vivo, as microglia rarely display a significant bias toward either phenotype.

    “Although the M1 and M2 categories have been helpful for conceptualizing microglia activities in vitro, it is increasingly accepted that the M1/M2 paradigm is inadequate to describe microglia and macrophage activation in vivo, as microglia rarely display a significant bias toward either the M1 or M2 phenotype.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Microglia are crucial for protection against NMDA-induced toxicity, in part because ATP released by damaged neurons activates microglial P2X7, inducing TNF-α secretion that tempers NMDA-induced toxicity.

    “Recent studies of organotypic hippocampal slice cultures have shown that microglia are crucial for protection against NMDA-induced toxicity (84). ATP released by damaged neurons activates the microglia receptor P2X7, inducing secretion of TNF-α, which tempers NMDA-induced toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] source

  • It may state two separate claims as one.

    Interpretationreasoning

    Some microglia markers may be modulated by activation and/or expressed in other cell types outside the CNS, so they may not be suitable for unequivocally identifying or targeting tissue-resident microglia.

    “Though helpful, some of these markers may be modulated by activation and/or expressed in other cell types outside of the CNS; therefore, they may not be suitable for unequivocally identifying or targeting tissue-resident microglia.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Aging microglia display signs of dystrophy, including reduced ramification and short, tortuous, swollen processes, and their ability to survey the brain and respond to insults declines with aging.

    “However, aging microglia display signs of dystrophy, including reduced ramification and short, tortuous, swollen processes (58). The ability of microglia to survey the brain and respond to insults also declines with aging (59).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] source
    • cites [59] source

  • It may state two separate claims as one.

    Premisecitation

    Depletion of microglia in mice engineered to express diphtheria toxin receptor in microglia caused a significant reduction in motor-learning-dependent glutamatergic excitatory synapses and impaired performance in multiple learning tasks, and this plasticity depended on BDNF secretion activating neuronal Trk.

    “Administration of DT and subsequent depletion of microglia in these mice caused a significant reduction in motor-learning-dependent glutamatergic excitatory synapses and impaired performance in multiple learning tasks. In this model, microglia-induced synaptic plasticity depended on BDNF secretion, which activated neuronal Trk, a key mediator of synaptic plasticity (Figure 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisenone given

    Alzheimer disease is the most common form of senile dementia, characterized by lesions consisting of extracellular masses of amyloid β peptides and intracellular bundles of fibrillar Tau protein.

    “AD is the most common form of senile dementia, characterized by lesions consisting of extracellular masses of amyloid β (Aβ) peptides and intracellular bundles of fibrillar Tau protein.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    An important effect of ApoE is enhancement of phagocytosis of Aβ aggregates by microglia while tempering their inflammatory responses.

    “Although ApoE is likely to influence AD through multiple mechanisms, an important effect is enhancement of phagocytosis of Aβ aggregates by microglia while tempering their inflammatory responses (102) (Figure 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] source

  • It may state two separate claims as one.

    Premisecitation

    In transgenic AD mouse models expressing human APP and presenilin 1 mutations, loss of NLRP3, TLR, and IL-1beta signaling reduces amyloid-beta deposition and prevents cognitive defects.

    “Lack of NLRP3, TLR, and IL-1β signaling in transgenic mouse models of AD that express human APP and presenilin 1 mutations, attenuates Aβ deposition and prevents cognitive defects (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

  • It may state two separate claims as one.

    Premisecitation

    TREM2 is a transmembrane glycoprotein expressed in myeloid cells that transmits intracellular signals through the adapters DAP12 and DAP10.

    “TREM2 is transmembrane glycoprotein expressed in myeloid cells that transmits intracellular signals through two associated transmembrane adapters, DAP12 (also known as Tyrobp) and DAP10 (Hcst) (26, 111, 112).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] source
    • cites [111] source
    • cites [112] Xing J, 2015, Res. Rep. Biochem.

  • It may state two separate claims as one.

    Interpretationnone given

    Neurodegenerative diseases hinge not only on misfolding of endogenous proteins but also on protein clearance; an imbalance between generation and disposal of misfolded proteins leads to irreversible autopropagation.

    “Neurodegenerative diseases hinge not only on misfolding of endogenous proteins, but also on protein clearance. Imbalance between generation and disposal of misfolded proteins leads to irreversible autopropagation.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Prion diseases are associated with activation of microglia and astrocytes, which contribute to PrPSc clearance.

    “Prion diseases are associated with activation of microglia and astrocytes, which contribute to PrPSc clearance.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Microglia can alter the course of neurodegeneration by clearing misfolded proteins by phagocytosis or, conversely, by releasing inflammatory mediators that promote protein aggregation and neuron damage.

    “Microglia can alter the course of neurodegeneration by clearing misfolded proteins by phagocytosis or, conversely, by releasing inflammatory mediators that promote protein aggregation and neuron damage (Figure 3).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The ApoE4 allele is strongly associated with an increased risk of Alzheimer disease, whereas the ApoE2 allele is associated with protection.

    “Subsequent studies in sporadic AD revealed that a polymorphism of apolipoprotein E (ApoE), the ApoE4 allele, is strongly associated with an increased risk of AD, whereas the ApoE2 allele is associated with protection (101).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] source

  • It may state two separate claims as one.

    Premisecitation

    Chronic stimulation of microglia by amyloid-beta can be harmful and cause prolonged inflammation.

    “chronic stimulation of microglia by Aβ may be deleterious and cause prolonged inflammation (Figure 3) (17)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

  • It may state two separate claims as one.

    Premisecitation

    DAP12 recruits the kinase Syk, which activates downstream mediators including PLC-gamma, PI-3K, and ERK.

    “DAP12 recruits the protein tyrosine kinase Syk, which activates multiple downstream signaling mediators, including PLC-γ, PI-3K, and ERK (111, 112).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] source
    • cites [112] Xing J, 2015, Res. Rep. Biochem.

  • It may state two separate claims as one.

    Premisecitation

    TREM2 binds polyanions, phospholipids, sulfatides, apoptotic-cell phospholipids, HDL and LDL particles, and ApoE.

    “TREM2 binds polyanions, particularly phospholipids and sulfatides that may be exposed in the brain during Aβ accumulation due to neuronal cell apoptosis and myelin damage (114).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [114] source
    • cites [115] 115. Song W, Hooli B, Mullin K, Jin SC, Cella M, et al. 2016. Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement . In press. https://doi.org/10.1016/j.jalz.2016.07.004 source
    • cites [116] source

  • It may state two separate claims as one.

    Premisecitation

    The rare R47H variant of TREM2 is associated with increased Alzheimer disease risk and impairs TREM2 binding to many phospholipid ligands.

    “A rare arginine 47 histidine (R47H) variant of TREM2 is associated with an increased risk for AD (107, 108). This variant impairs binding of TREM2 to many phospholipid ligands (114, 125).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [107] source
    • cites [108] source
    • cites [114] source

  • It may state two separate claims as one.

    Premisecitation

    TREM2 promotes proliferation, survival, and phagocytosis of apoptotic cells.

    “TREM2 promotes proliferation (119), survival (119), and phagocytosis of apoptotic cells (120–122).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [119] source
    • cites [120] source
    • cites [121] source
    • cites [122] source

  • It may state two separate claims as one.

    Premisecitation

    A CD33 variant associated with increased Alzheimer disease risk is expressed at relatively high levels, increasing CD33 inhibitory effects on myeloid functions such as internalization of amyloid-beta 1-42.

    “a CD33 variant associated with an increased risk for AD is expressed at relatively high levels, increasing CD33 inhibitory effects on myeloid functions, such as internalization of the Aβ1–42 peptide (137).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] source

  • It may state two separate claims as one.

    Interpretationreasoning

    TREM2 signaling helps protect against Alzheimer disease but can cause harm when excessive.

    “suggesting that TREM2 signaling helps protect against AD but can cause harm in excess.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    In an Alzheimer disease mouse model, complement was activated before plaque deposition and microglia were responsible for complement-mediated synaptic loss.

    “in a mouse model of AD, complement was activated before plaque deposition and microglia were responsible for complement-mediated synaptic loss (139).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] source

  • It may state two separate claims as one.

    Premisecitation

    Weakening of microglial barriers around amyloid-beta facilitates early spreading and invasiveness of fibrillar amyloid, followed by later amyloid-beta accumulation during disease progression.

    “This weakening of microglial barriers around Aβ facilitates spreading and invasiveness of fibrillar amyloid at early stages of disease (130, 131) followed by later accumulation of Aβ during disease progression (114, 132).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [130] source
    • cites [131] source
    • cites [114] source

  • It may state two separate claims as one.

    Premisecitation

    Cerebrospinal fluid levels of soluble TREM2 are a potential biomarker for microglial activity in early-stage Alzheimer disease and correlate with neuronal injury markers.

    “cerebrospinal fluid levels of soluble TREM2 are a potential biomarker for microglia activity in early-stage AD and correlate with neuronal injury markers (135, 136).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [135] source
    • cites [136] source

  • It may state two separate claims as one.

    Premisecitation

    Restraining microglial activation by ablating NF-kappaB signaling rescues motor neurons from microglia-mediated death in vitro and extends survival of SOD1G93A mice.

    “restraining microglial activation by ablating NF-κB signaling rescued motor neurons from microglia-mediated death in vitro and extended survival of SOD1G93A mice (151).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] source

  • It may state two separate claims as one.

    Interpretationreasoning

    Microglia in amyotrophic lateral sclerosis have a distinct gene-expression signature that does not fit the M1/M2 paradigm and partially overlaps with other neurodegenerative diseases.

    “Thus, microglia in ALS have a distinct gene-expression signature that does not fit the M1/M2 paradigm but reflects microglial response to protein aggregates, stress, and neuronal cell death and partially overlaps with that of other neurodegenerative diseases”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    C9orf72 is required for normal myeloid cell function, and altered microglial function may contribute to neurodegeneration in carriers of C9orf72 expansion.

    “C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in carriers of C9orf72 expansion (153).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] source

  • It may state two separate claims as one.

    Premisecitation

    LRRK2-deficient rats have no significant loss of neurons and reduced numbers of activated myeloid cells in the substantia nigra.

    “LRRK2-deficient rats, in contrast, had no significant loss of neurons and reduced numbers of activated myeloid cells in the substantia nigra (160).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] source

  • It may state two separate claims as one.

    Premisecitation

    In humans, rare gain-of-function mutations of TBK1 are associated with normal tension glaucoma and may affect autophagy and phagocytic functions of microglia.

    “In human, rare gain-of-function mutations of TBK1 are associated with normal tension glaucoma. These mutations may affect autophagy and phagocytic functions of microglia (157).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] source

  • It may state two separate claims as one.

    Premisecitation

    Mice lacking Hoxb8 in all cells or only in myeloid and endothelial cells spend twice as much time grooming as littermates, leading to hair loss and skin lesions reminiscent of trichotillomania.

    “Mice lacking the homeobox gene Hoxb8 in all cells or only in myeloid and endothelial cells spend twice as much time grooming as do their littermates, leading to hair loss and skin lesions reminiscent of a human compulsive disorder known as trichotillomania (175).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [175] source

  • It may state two separate claims as one.

    Premisecitation

    Modulation of inflammation through the adenosine A2A receptor prevents neuroinflammation and protects retinal ganglion cells in vitro and in vivo.

    “Modulation of inflammation through the adenosine A2A receptor (A2AR) also prevented neuroinflammation and protected retinal ganglion cells in vitro and in vivo (174).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] source

  • It may state two separate claims as one.

    Premisecitation

    Studies reveal microglial activation in depressed patients, with greater magnitude in individuals who completed suicide.

    “Studies have revealed microglial activation in depressed patients, with a greater magnitude of activation in individuals who completed suicide (181–183)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [181] source
    • cites [182] source
    • cites [183] source

  • It may state two separate claims as one.

    Premisecitation

    In a mouse model of glaucoma, the complement pathway is upregulated before retinal ganglion cell death, and C1q deficiency protects from glaucoma.

    “In a mouse model of glaucoma, the complement pathway is upregulated before retinal ganglion cell death, while induction of C1q deficiency protects from glaucoma (69).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] source

  • It may state two separate claims as one.

    Interpretationreasoning

    M1 activation is not always detrimental, nor is M2 activation necessarily beneficial.

    “Moreover, M1 activation is not always detrimental nor is M2 activation necessarily beneficial.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Cholesterol-lowering statins and other metabolic drugs have been reported to subdue inflammatory microglial functions and improve cognitive function in Alzheimer disease mouse models, but human observational and randomized trials show conflicting results.

    “Cholesterol-lowering statins (195) and other metabolic drugs (196) have been reported to subdue inflammatory microglial functions and have beneficial effects on cognitive function in mouse models of AD. Moreover, the results of observational and randomized trials in humans have shown conflicting results (195).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [195] source
    • cites [196] source

  • It may state two separate claims as one.

    Premisecitation

    In Alzheimer disease models, M1 functions promote removal of amyloid plaques, while M2 functions may facilitate amyloid spreading.

    “In models of AD, M1 functions promote removal of amyloid plaques, while M2 functions may facilitate amyloid spreading (187).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] source

  • It may state two separate claims as one.

    Premisecitation

    Oral administration of the RXR agonist bexarotene in an Alzheimer disease mouse model facilitates rapid clearance of soluble amyloid-beta, linked to increased ApoE levels and TREM2 expression.

    “Oral administration of the RXR agonist bexarotene in a mouse model of AD facilitated rapid clearance of soluble Aβ (103). The therapeutic effect was linked to the induction of increased levels of ApoE. Moreover, a recent study showed that bexarotene induces TREM2 expression in microglia (197).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] source
    • cites [197] source

  • It may state two separate claims as one.

    Interpretationreasoning

    Therapeutic agents that target microglia may have beneficial effects but also adverse effects.

    “Thus, therapeutic agents that target microglia may have beneficial effects but also adverse effects.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Microglial autophagy facilitates clearance of extracellular amyloid-beta fibrils and reduces amyloid-beta-induced NLRP3 activation.

    “one study showed that microglial autophagy facilitates clearance of extracellular Aβ fibrils and reduces Aβ-induced NLRP3 activation (200).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] source

  • It may state two separate claims as one.

    Premisecitation

    M1 microglia may be neurotoxic in some cases but promote axonal regeneration in others.

    “M1 microglia may be neurotoxic in some cases but promote axonal regeneration in others (186).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] source

  • It may state two separate claims as one.

    Premisecitation

    Humanized antibodies targeting misfolded proteins such as amyloid-beta have been developed and are being tested in clinical trials.

    “Humanized antibodies that target misfolded proteins, such as Aβ, have been developed and are currently being tested in clinical trials (188, 189).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188] source
    • cites [189] source

  • It may state two separate claims as one.

    Interpretationreasoning

    Microglial phagocytosis can be a double-edged sword in neurodegeneration: it may clear misfolded proteins early but may spread pathogenic seeds or prune synapses later.

    “Microglial phagocytosis can also be a double-edged sword in neurodegeneration. On one hand, it may facilitate the clearance of misfolded proteins at disease onset; on the other hand, it may facilitate the spreading of pathogenic seeds during disease progression if protein digestion is impaired, or contribute to synapse loss if too many synapses are pruned.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Microglial autophagy is involved in synaptic pruning and regulates behavior.

    “Another recent study showed that microglial autophagy is involved in synaptic pruning and regulates behavior (201).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] 201. Kim HJ, Cho MH, Shim WH, Kim JK, Jeon EY, et al. 2016. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol. Psychiatry. In press. https://doi.org/10.1038/mp.2016.103 source

  • Probably not a substantial claim.

    Interpretationreasoning

    Given the role of complement in synaptic loss and the association of CR1 mutations with Alzheimer disease, targeting complement components may be valuable for both amyloid-beta and Tau pathologies.

    “given the role of complement in synaptic loss and the association of CR1 mutations in AD, targeting of complement components may be a valuable option for both Aβ and Tau pathologies.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Because Alzheimer disease is associated with hypomorphic TREM2 mutations and hypermorphic CD33 mutations, antibodies activating TREM2 or blocking CD33 might help correct microglial dysfunction.

    “Since AD is associated with hypomorphic mutations of TREM2 and hypermorphic mutations of CD33, antibodies activating TREM2 or blocking CD33 might be helpful in correcting microglial dysfunction.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Two recent studies showed that brain-engrafted bone marrow-derived cells either do not acquire microglial functions or do so only after a long time.

    “two recent studies showed that brain-engrafted bone marrow–derived cells either do not acquire microglial functions or do so only after a long time (202, 203).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [202] source
    • cites [203] source
57 of 57

  • The paper relies on this without support.

    Microglia can be stimulated by DAMPs such as ATP and DNA.

    “Moreover, microglia can be stimulated by DAMPs, such as ATP and DNA.”

  • The paper relies on this without support.

    In mice, CD33 deficiency reduces insoluble amyloid-beta 1-42 and amyloid plaques.

    “Moreover, in mice, CD33 deficiency is associated with reduced levels of insoluble Aβ1–42 in the brain as well as fewer amyloid plaques.”
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?

  • CSF1R mutations reduce microglia numbers in the human brain.

    “CSF1R mutations also reduce microglia numbers in the human brain”

    From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Colonna and Butovsky, 2017

    The Development of CNS Mononuclear Phagocytes section (page not provided) says genetic defects in CSF1R drastically reduce microglia numbers. It does not establish that this reduction occurs in the human brain; the cited studies on CSF1R defects are in mice. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Under pathological conditions, microglia can acquire a detrimental pro-inflammatory phenotype that actively contributes to neuroinflammation, express genes involved with phagocytosis and lipid metabolism, and phagocytose unwanted material and synapses.

    “Indeed, under pathological conditions, microglia can acquire a detrimental pro-inflammatory phenotype that actively contributes to neuroinflammation, express genes involved with phagocytosis and lipid metabolism [343], and phagocytose unwanted material and synapses [344].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [344]

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

    Experimental — accuracy not yet measured

  • ApoE facilitates the microglial response to amyloid plaque pathology.

    “It has been reported that ApoE facilitates the microglial response to amyloid plaque pathology (31).”

    From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [31]

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

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

    From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [28]

  • Microglia clear apoptotic cells via efferocytosis, contributing to brain homeostasis.

    “Microglia also contribute to the maintenance of brain homeostasis by clearing apoptotic cells in the brain via efferocytosis (27–29).”

    From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [28]

Citations

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 4

  1. Appel SH, 2011, Acta Myol, 30, 4
  2. Xing J, 2015, Res. Rep. Biochem., 5, 89
  3. 127. Paloneva J, Autti T, Hakola P, Haltia MJ. 2002. Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) . GeneReviews, updated Mar. 12, 2015, Univ. Wash., Seattle. https://www.ncbi.nlm.nih.gov/books/NBK1197/
  4. Nussenblatt RB, 2009, Curr. Opin. Investig. Drugs, 10, 434

Cited by

Sorted by citations

Related

Metadata

Authors
Colonna, M., & Butovsky, O.
Affiliations
  • Washington University in St. Louis (US)
  • Brigham and Women's Hospital (US)
ORCID
Venue
Annual Review of Immunology
Publisher
Annual Reviews
Published
2017-04-26
Volume
35
Issue
1
Pages
441-468
ISSN
  • 0732-0582 (ISSN-L)
  • 1545-3278
DOI
10.1146/annurev-immunol-051116-052358
PMC
PMC8167938
OpenAlex
W2527645962
Cited by
2,894
References
205
Citations by year
2026: 439 · 2025: 510 · 2024: 526 · 2023: 385 · 2022: 304 · 2021: 264 · 2020: 195 · 2019: 132 · 2018: 105 · 2017: 29
FWCI
12.12
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • ALS Association (ALSA2087)
  • Multiple Sclerosis Society (5092A1)
  • National Institutes of Health
  • National Institute on Aging (R01AG051812, RF1AG051485)
  • National Institute of Neurological Disorders and Stroke (R01NS088137)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
microglia, neurodegeneration, neuroinflammation, microglial homeostasis, microglial phenotype, inflammatory cytokines, brain development, brain aging, microglia-targeted therapy, neurodegenerative diseases, synaptic pruning, phagocytosis
MeSH terms
Animals, Biological Therapy, Brain, Central Nervous System, Homeostasis, Humans, Cytokines, Microglia, Neurodegenerative Diseases, Neurogenic Inflammation

About these checks

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

A language model drew the claims from the paper on 2026-10-05, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-05 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

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 ›

Are you an author, or do you see a problem with this page? Request a review