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Cited by 1,044Neuroinflammation and Neurodegeneration MechanismsRedox biology and oxidative stressNeurological Disease Mechanisms and Treatments

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

Open access
Simpson, Dominic S. A., Oliver, Peter L.·2020·Antioxidants
DOI 10.3390/antiox9080743PMC PMC7463655
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Abstract

Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation. However, the molecular mechanisms linking DAM activation and OS have not been well-defined; thus targeting these cells for clinical benefit has not been possible. In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2) and activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature. Additionally, ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation; thus intracellular ROS signalling may underlie excessive inflammation and OS. Targeting key kinases in the inflammatory response could cease inflammation and promote tissue repair. Expression of antioxidant proteins in microglia, such as NADPH dehydrogenase 1 (NQO1), is promoted by transcription factor Nrf2, which functions to control inflammation and limit OS. Lipid droplet accumulating microglia (LDAM) may also represent a double-edged sword in neurodegenerative disease by sequestering peroxidised lipids in non-pathological ageing but becoming dysregulated and pro-inflammatory in disease. We suggest that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation. Finally, we discuss recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that microglial reactive oxygen species (ROS), generated mainly by NOX2 and NOX4, link neuroinflammation and oxidative stress in neurodegenerative disease, with ROS also acting as second messengers and lipid droplet-accumulating microglia contributing to pathology. It proposes targeting microglial NOX, Nrf2-driven antioxidant pathways, and unbiased disease-relevant drug discovery.

Key findings

  • NOX2 (CYBB) is the most highly expressed NOX isotype transcript in human and mouse brain microglia, with NOX4 second-highest at a much lower level; NOX2 activation in disease-associated microglia is associated with DAMP signalling, inflammation, and amyloid plaque deposition, especially in the cerebrovasculature.
  • ROS from both NOX and mitochondria may act as second messengers to propagate immune activation: H₂O₂ can activate NFκB, and suppressing mitochondrial ROS with mitoTEMPO reduced MAPK/NFκB activation and pro-inflammatory factors (TNFα, IL1β, IL6, iNOS, Cox-2) in LPS-stimulated microglia.
  • Nrf2 controls antioxidant genes such as NQO1 and GSTs in microglia; Nrf2 deficiency promotes inflammatory markers (IL6, Cox2, iNOS) and inhibits anti-inflammatory markers, while sulforaphane enhances Nrf2, limits pro-inflammatory microglial markers, and confers neuroprotection.
  • Lipid droplet-accumulating microglia (LDAM) may be a double-edged sword: ROS/JNK drive lipid droplet formation in flies, antioxidant treatment or SOD1 expression reduces it, and GRN−/− mice show ROS-generating, pro-inflammatory LDAM defective in phagocytosis; ToxSeq identified a ROS-positive microglial signature rescued by acivin in EAE.

Methods

  • Narrative review; no primary data, experimental sample, or statistical analysis are reported.
  • The paper synthesizes literature on microglial NOX/ROS biology, oxidative stress, neuroinflammation, lipid droplet-accumulating microglia, antioxidant regulation, and therapeutic strategies.
  • It discusses evidence from human post-mortem tissue, rodent models, cell lines, single-cell RNA-seq, and drug-screening studies, and proposes future directions including cell-specific NOX manipulation.

Limitations

  • The paper does not state limitations of its own review; it repeatedly notes limitations in the underlying literature, including lack of stringent controls and specific antibodies for NOX expression studies, possible artefactual NOX1 expression in Cx3cr1-EGFP reporter mice, and a human microglial cell line lacking NOX2.
  • It also notes that apocynin specificity for NOX4 has been questioned, mitoTEMPO selectivity is questioned especially at higher concentrations, and a causal relationship between ROS and NFκB activation in microglia remains undetermined.
  • Evident from the text: as a narrative review, no systematic search or formal quality assessment is described, and many conclusions rely on preclinical models or immortalized cells, with calls for validation in primary and iPSC-derived microglia.

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

Integrity signals

Registry

Crossref · 10.3390/antiox9080743

Cites

194 of 194 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 222 cited sources checked · 0 supported · 0 flagged

  • Interpretationcitation

    This identifies a mechanistic link between microglial activation in AD and the development of tau pathology.

    “Critically, this identifies a mechanistic link between microglial activation in AD and the development of tau pathology.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature.

    “activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    NOX2 mediates the oxidative burst during phagocytosis or in response to pro-inflammatory signals such as IFNγ in peripheral phagocytes.

    “NOX is best characterised in peripheral phagocytes (macrophages and neutrophils), where NOX2 or Phox (phagocyte NOX, gp91phox) mediates the oxidative burst during phagocytosis or in response to pro-inflammatory signals, such as IFNγ [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Nathan, 1986, Secretion of toxic oxygen products by macrophages: Regulatory cytokines and their effects on the oxidase, Ciba Found. Symp.

      Not checked in the free run.

  • Interpretationreasoning

    Intracellular ROS signalling may underlie excessive inflammation and oxidative stress.

    “thus intracellular ROS signalling may underlie excessive inflammation and OS.”
    Quote in the paperSubstantial claim
  • Premisecitation

    There is a strong correlation between immune activation and oxidative damage in neurodegenerative disease.

    “since there is a strong correlation between immune activation and oxidative damage in neurodegenerative disease [42,43,44]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Heneka, 2015, Neuroinflammation in Alzheimer’s disease, Lancet Neurol. source

      Not checked in the free run.

    • cites [43] Trushina, 2017, Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease, J. Alzheimers Dis. JAD source

      Not checked in the free run.

    • cites [44] Reiss, 2018, Amyloid toxicity in Alzheimer’s disease, Rev. Neurosci. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 24
  • May combine two claims. 61

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

    Interpretationnone given

    ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation.

    “ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microglia respond to DAMPs by producing ROS, which becomes elevated and sustained in disease.

    “Furthermore, microglia respond to damage-associated molecular patterns (DAMPs)—molecules released from damaged cells—by the production of ROS, which becomes elevated and sustained in disease [27,28,29].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Veerhuis, 1996, Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity, J. Neurochem. source

      Not checked in the free run.

    • cites [28] Klegeris, 1997, beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate, J. Neurosci. Res. source

      Not checked in the free run.

    • cites [29] Schilling, 2011, Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia, J. Cell. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Alzheimer's disease (AD), microglia surround amyloid plaques and respond to amyloid-β with a pro-inflammatory phenotype characterised by cytokine expression (IL1β, IL6, TNFα) that may initially limit amyloidosis but likely becomes overzealous and neurotoxic.

    “In Alzheimer’s disease (AD), the most common form of dementia, microglia surround amyloid plaques and respond to amyloid-β with a pro-inflammatory phenotype characterised by cytokine expression (e.g., interleukins (IL) 1β and 6 and tumour necrosis factor α (TNFα)) that may initially limit amyloidosis but likely becomes overzealous and neurotoxic [12,13,14].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Mielke, 2011, Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease, Am. J. Pathol. source

      Not checked in the free run.

    • cites [13] Hickman, 2008, Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer’s Disease Mice, J. Neurosci. source

      Not checked in the free run.

    • cites [14] Zhao, 2017, Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease, Mol. Neurodegener. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation.

    “DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microglia phagocytose α-synuclein and become pro-inflammatory, expressing cytokines (IL1β, IL6, TNFα), ROS and COX2.

    “Microglia also phagocytose α-synuclein, the constituent protein of Lewy bodies in Parkinson’s and Lewy Body dementias, and become pro-inflammatory in the process, expressing cytokines (IL1β, IL6, TNFα), reactive oxygen species (ROS) and prostaglandin synthesising cyclooxygenase 2 (COX2) [24,25,26].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Croisier, 2005, Microglial inflammation in the parkinsonian substantia nigra: Relationship to alpha-synuclein deposition, J. Neuroinflamm. source

      Not checked in the free run.

    • cites [25] Su, 2008, Synuclein activates microglia in a model of Parkinson’s disease, Neurobiol. Aging source

      Not checked in the free run.

    • cites [26] Kim, 2013, Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia, Nat. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxidative stress is a hallmark of AD, indicated by lipid peroxidation, protein oxidation and mitochondrial DNA damage.

    “Since oxidative stress is a hallmark of AD, indicated by lipid peroxidation [30,31,32,33], protein oxidation [34,35] and mitochondrial DNA damage [36]”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [30] Sung, 2004, Lipid peroxidation and oxidative imbalance: Early functional events in Alzheimer’s disease, J. Alzheimers Dis. JAD source

      Not checked in the free run.

    • cites [31] Clark, 2000, Increased 8,12-iso-iPF2α-VI in Alzheimer’s disease: Correlation of a noninvasive index of lipid peroxidation with disease severity, Ann. Neurol. source

      Not checked in the free run.

    • cites [32] Lovell, 1995, Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease, Neurology source

      Not checked in the free run.

    • cites [33] Subbarao, 1990, Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro, J. Neurochem. source

      Not checked in the free run.

    • cites [34] Hensley, 1995, Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation, J. Neurochem. source

      Not checked in the free run.

    • cites [35] Smith, 1991, Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [36] Mecocci, 1994, Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease, Ann. Neurol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    Elevated and dysregulated ROS production from DAM contributes to oxidative stress, leading to neuronal death.

    “it is hypothesised that elevated and dysregulated ROS production from DAM contributes to oxidative stress, leading to neuronal death.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neuroinflammation and oxidative stress are hallmarks of neurodegeneration and contribute to disease progression.

    “Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Heneka, 2015, Neuroinflammation in Alzheimer’s disease, Lancet Neurol. source

      Not checked in the free run.

    • cites [43] Trushina, 2017, Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease, J. Alzheimers Dis. JAD source

      Not checked in the free run.

    • cites [44] Reiss, 2018, Amyloid toxicity in Alzheimer’s disease, Rev. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Data suggest NOX2 is a driver of excessive inflammation in response to neuronal injury and may impede inflammatory resolution in vivo.

    “Nevertheless, data suggest NOX2, along with mediating sustained ROS production, is a driver of excessive inflammation in response to neuronal injury and may impede inflammatory resolution in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NOX activation is evident in the AD brain; the NOX2 regulatory subunits p47phox and p67phox are translocated from cytosolic to membranous fractions of AD brains, suggesting NOX2 activation.

    “NOX activation is evident in the AD brain. The NOX2 regulatory subunits, p47phox and p67phox, are translocated from the cytosolic to the membranous fractions of AD brains, suggesting NOX2 activation [113].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Shimohama, 2000, Activation of NADPH oxidase in Alzheimer’s disease brains, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    NOX4 is expressed in the mammalian brain, but specific proteomic expression in microglia is unknown.

    “NOX4 is expressed in the mammalian brain, however specific proteomic expression in microglia is unknown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NOX1 transcript and protein expression have been described in microglia isolated from Cx3cr1-EGFP reporter mice, although expression has not been demonstrated in the mouse brain elsewhere.

    “NOX1 transcript and protein expression have been described in microglia isolated from Cx3cr1-enhanced green fluorescent protein (EGFP) reporter mice [77], although expression has not been demonstrated in the mouse brain elsewhere, to our knowledge [65].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] Gervais, 2008, Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase, J. Neurosci. source

      Not checked in the free run.

    • cites [65] Sorce, 2009, NOX Enzymes in the Central Nervous System: From Signaling to Disease, Antioxid. Redox Signal. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unlike mitochondrial ROS, which are by-products of oxidative phosphorylation, ROS generated from NOX are deliberate and part of the antimicrobial armoury of phagocytes.

    “Unlike mitochondrial ROS, which are by-products of oxidative phosphorylation, ROS generated from NOX are deliberate and part of the antimicrobial armoury of phagocytes [58].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Darrah, 2000, Cooperation between reactive oxygen and nitrogen intermediates in killing of Rhodococcus equi by activated macrophages, Infect. Immun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expression of cytosolic regulatory subunits of NOX2 (p67phox, p47phox, p40phox) is positively correlated with disease progression and oxidative stress in AD, whilst expression of membrane-bound flavocytochrome b558 subunits (gp91phox, p22phox) is stable.

    “Indeed, the expression of cytosolic regulatory subunits of NOX2 (p67phox, p47phox and p40phox) is positively correlated with disease progression and oxidative stress in AD, whilst expression of membrane-bound flavocytochrome b558 subunits (gp91phox and p22phox) is stable [68].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Ansari, 2011, NADPH-oxidase activation and cognition in Alzheimer disease progression, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    DAMP signalling on these receptors may underpin excessive ROS production by inflammatory-related phagocytic activation and prime a vicious cycle of DAMP-induced neuronal damage by oxidative stress.

    “Hence, DAMP signalling on these receptors may underpin excessive ROS production by inflammatory-related phagocytic activation and prime a vicious cycle of DAMP-induced neuronal damage by oxidative stress [86,96] (Figure 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [86] Hou, 2018, Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway, Redox Biol. source

      Not checked in the free run.

    • cites [96] Bell, 2013, Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon activation by assembly of multiple subunits, NOX enzymes generate the superoxide radical; NOX4 is the exception, being constitutively active, independent of regulatory subunits, and mostly producing H2O2.

    “Upon activation by the assembly of multiple subunits, NOX enzymes generate the superoxide radical (O2•–). The exception is NOX4, which is constitutively active, independent of co-expression with regulatory subunits, and mostly produces H2O2 [56,57].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Geiszt, 2000, Identification of renox, an NAD(P)H oxidase in kidney, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [57] Shiose, 2001, A novel superoxide-producing NAD(P)H oxidase in kidney, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of NOX4 in human microglial cell line clone 3 suppresses both ROS and IL6 production, confirming a link between NOX4 activation and pro-inflammatory cytokine expression.

    “Knockdown of NOX4 in these cells suppresses both ROS and interleukin (IL)6 production, confirming a link between NOX4 activation and pro-inflammatory cytokine expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Li, 2009, NOX4 expression in human microglia leads to constitutive generation of reactive oxygen species and to constitutive IL-6 expression, J. Innate Immun. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    NOX2 is expressed robustly in both human and murine microglia and the adult CNS and throughout development, indicating a strong evolutionary requirement for its expression in the CNS.

    “NOX2 is expressed robustly in both human and murine microglia and the adult CNS and throughout development, indicating a strong evolutionary requirement for its expression in the CNS.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Loss-of-function mutations in NOX2 result in chronic granulomatous disease, characterised by recurrent infections caused by impaired phagocytosis.

    “Loss-of-function mutations in NOX2 result in chronic granulomatous disease, a rare syndrome described in 1957 and characterised by recurrent infections caused by impaired phagocytosis [46,47,48].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Berendes, 1957, A fatal granulomatosus of childhood: The clinical study of a new syndrome, Minn. Med.

      Not checked in the free run.

    • cites [47] Quie, 1967, In vitro bactericidal capacity of human polymorphonuclear leukocytes: Diminished activity in chronic granulomatous disease of childhood, J. Clin. Investig. source

      Not checked in the free run.

    • cites [48] Baehner, 1967, Leukocyte oxidase: Defective activity in chronic granulomatous disease, Science source

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  • May combine two claims.

    Interpretationcitation

    The human microglial cell line clone 3 does not express NOX2, which calls into question the validity of the model since NOX2 is the most highly expressed isotype in both human and murine microglia.

    “Interestingly, however, this particular cell line does not express NOX2; this calls into question the validity of the model since NOX2 is the most highly expressed isotype in both human and murine microglia [72,73].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Zhang, 2014, An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex, J. Neurosci. source

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    • cites [73] Zhang, 2016, Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse, Neuron source

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  • May combine two claims.

    Premisecitation

    CR3, which is upregulated in human AD-associated microglia, contributes to persistent inflammation, NOX2 activation and O2•- release in response to DAMPs, such as amyloid-β.

    “CR3, which is upregulated in human AD-associated microglia, contributes to persistent inflammation, NOX2 activation and O2•- release in response to DAMPs, such as amyloid-β [85,98,99,100].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [85] Fu, 2012, Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia, Glia source

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    • cites [98] Zhang, 2011, Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity, J. Neuroinflamm. source

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    • cites [99] Hu, 2008, Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease, J. Immunol. source

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    • cites [100] Akiyama, 1990, Brain microglia constitutively express beta-2 integrins, J. Neuroimmunol. source

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  • May combine two claims.

    Premisecitation

    Pharmacological blockade or microglial-specific knockout of TLR4 or CR3 severely attenuates ROS production by NOX2, indicating NOX2 activation is of microglial origin.

    “Pharmacological blockade or microglial-specific knockout of TLR4 or CR3 severely attenuates ROS production by NOX2, indicating NOX2 activation is of microglial origin, despite reported expression of NOX2 in neurons [64,102,103].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [64] Cooney, 2013, Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury, J. Neuroinflamm. source

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    • cites [102] Levesque, 2013, The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function, J. Neurochem. source

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    • cites [103] Pei, 2007, MAC1 mediates LPS-induced production of superoxide by microglia: The role of pattern recognition receptors in dopaminergic neurotoxicity, Glia source

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

    Premisecitation

    The rate-limiting step of NOX2 activation is hypothesised to be serine-threonine phosphorylation of p47phox by p21 (cdc42/Rac1)-activated kinase-1.

    “The rate-limiting step of NOX2 activation is hypothesised to be serine-threonine phosphorylation of p47phox by p21 (cdc42/Rac1)-activated kinase-1 [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Roepstorff, 2008, Stimulus-dependent Regulation of the Phagocyte NADPH Oxidase by a VAV1, Rac1, and PAK1 Signaling Axis, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    NOX is activated in in vivo models of AD and offsetting this upregulation may limit neurodegeneration and cognitive impairment.

    “Nonetheless, NOX is activated in in vivo models of AD and offsetting this upregulation may limit neurodegeneration and cognitive impairment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Evidence from mammalian studies indicates that NOX activation in response to amyloid-β contributes to neurodegeneration and is associated with cerebrovascular pathology.

    “Evidence from mammalian studies indicates that NOX activation in response to amyloid-β contributes to neurodegeneration and is associated with cerebrovascular pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Age-related amyloid deposition, microgliosis and ROS production were dependent on NOX2 expression and findings correlated with post-mortem tissue from young and aged human samples.

    “Furthermore, age-related amyloid deposition, microgliosis and ROS production were dependent on NOX2 expression and findings correlated with post-mortem tissue from young and aged human samples [125].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Geng, L., Fan, L.M., Liu, F., Smith, C., and Li, J.-M. (2020). Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging. Sci. Rep., 10. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia in AD brains strongly express gp91phox, implying NOX2 activation is localised to microglia in AD.

    “Further, microglia in AD brains strongly express gp91phox, implying NOX2 activation is localised to microglia in AD [119].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Gupta, 2010, NOX activity is increased in mild cognitive impairment, Antioxid. Redox Signal. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ-42 induces NOX2 expression in microglia and this response is accentuated in aged mice.

    “Indeed, Aβ-42 induces NOX2 expression in microglia and this response is accentuated in aged mice [125].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Geng, L., Fan, L.M., Liu, F., Smith, C., and Li, J.-M. (2020). Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging. Sci. Rep., 10. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglial activation by the TLR4 agonist LPS results in degradation of IκB, translocation of NFκB to the nucleus and activation of κB-containing DNA response elements, including TNFα, IL1β and cyclooxygenase-2 (COX2).

    “For example, microglial activation by the TLR4 agonist, LPS, results in degradation of IκB, translocation of NFκB to the nucleus and activation of κB-containing DNA response elements, including TNFα, IL1β and cyclooxygenase-2 (COX2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Dresselhaus, E.C., and Meffert, M.K. (2019). Cellular Specificity of NF-κB Function in the Nervous System. Front. Immunol., 10. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a humanised APP/PS1 mouse, increased NOX activity and NOX4 expression were age-dependent and NOX activity was strongly correlated with cognitive impairment.

    “whilst neurovascular changes were not reported, increased NOX activity and NOX4 expression were age-dependent and NOX activity was, again, strongly correlated with cognitive impairment [117].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Gupta, 2011, Cognitive impairment in humanized APP×PS1 mice is linked to Aβ(1-42) and NOX activation, Neurobiol. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Amyloid-β stimulates NOX2 in rat microglia and peripheral phagocytes, whilst phagocytes isolated from patients with chronic granulomatosis disease do not respond to stimulation with amyloid-β.

    “Furthermore, amyloid-β stimulates NOX2 in rat microglia and peripheral phagocytes, whilst phagocytes isolated from patients with chronic granulomatosis disease (caused by a genetic deficiency of NOX2) do not respond to stimulation with amyloid-β [121].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Bianca, 1999, β-Amyloid Activates the O⨪2 Forming NADPH Oxidase in Microglia, Monocytes, and Neutrophils A POSSIBLE INFLAMMATORY MECHANISM OF NEURONAL DAMAGE IN ALZHEIMER’S DISEASE, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOX1 and 3 expression is increased in early AD, followed by upregulation of markers of mitochondrial dysfunction.

    “Also, NOX1 and 3 expression is increased in early AD, followed by upregulation of markers of mitochondrial dysfunction [114].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Wands, 2006, Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease, J. Alzheimers Dis. JAD source

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  • May combine two claims.

    Premisecitation

    In LPS-stimulated macrophages, lutein scavenges intracellular O2•- and H2O2 and reduces NFκB activation, whilst TLR4 signalling and MAPK activation remain.

    “In LPS-stimulated macrophages, the peripheral cousins of microglia, the antioxidant lutein scavenges intracellular O2•– and H2O2 and reduces NFκB activation, whilst TLR4 signalling and MAPK activation remained [146].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Kim, 2008, The non-provitamin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathways: Role of H2O2 in NF-κB activation, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NFκB activation by TLR4 signalling results in neuroinflammation and cognitive impairment.

    “NFκB activation by TLR4 signalling results in neuroinflammation and cognitive impairment [141,142].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [141] Wang, 2012, The transcriptional specificity of NF-κB dimers is coded within the κB DNA response elements, Cell Rep. source

      Not checked in the free run.

    • cites [142] Zhao, 2019, Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice, Sci. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a Pseudomonas aeruginosa macrophage activation model, knockdown of gp91phox or application of N-acetyl cysteine (NAC) reduced NFκB activation levels.

    “Knockdown of gp91phox or application of N-acetyl cysteine (the antioxidant, NAC) in infected macrophages reduced NFκB activation levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Li, H., Luo, Y.-F., Wang, Y.-S., Yang, Q., Xiao, Y.-L., Cai, H.-R., and Xie, C.-M. (2020, June 16). Using ROS as a Second Messenger, NADPH Oxidase 2 Mediates Macrophage Senescence via Interaction with NF-κB during Pseudomonas aeruginosa Infection. Available online: https://www.hindawi.com/journals/omcl/2018/9741838/. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p47phox and p67phox are not expressed in neurons or astrocytes isolated from rats, but cytosolic translocation of both subunits does occur in microglia.

    “However, p47phox and p67phox are not expressed in neurons or astrocytes isolated from rats, but cytosolic translocation of both subunits does occur in microglia [113].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Shimohama, 2000, Activation of NADPH oxidase in Alzheimer’s disease brains, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

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

    Premisecitation

    Microglial NFκB is a dimer of p50 (NFκB1) and p65 (Rel-A).

    “Microglial NFκB is a dimer of p50 (NFκB1) and p65 (Rel-A) [138,139] and is sequestered in the cytoplasm by inhibitor of κB (IκB).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [138] Wang, W.-Y., Tan, M.-S., Yu, J.-T., and Tan, L. (2015). Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann. Transl. Med., 3.

      Not checked in the free run.

    • cites [139] Zheng, 2011, Structural studies of NF-κB signaling, Cell Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GRN−/− mice display high numbers of LDAM which are ROS-generating and pro-inflammatory, yet defective in phagocytosis.

    “Interestingly, GRN−/− mice display high numbers of LDAM which are ROS-generating and pro-inflammatory, yet defective in phagocytosis [162].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source

      Not checked in the free run.

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

    Premisenone given

    The MAPK family includes extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPKs.

    “The family includes extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPKs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Endogenous ROS derived from mitochondria are critical mediators of the neuroimmune response to LPS, as well as exogenous ROS, i.e., from neuronal damage.

    “This identifies endogenous ROS derived from mitochondria as critical mediators of the neuroimmune response to LPS, as well as exogenous ROS, i.e., from neuronal damage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Park, 2015, Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways, Neurosci. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL1 signalling results in activation of the small G-protein Ras, which in turn activates MKK6, resulting in activation of p38 MAPK.

    “For example, IL1 signalling results in activation of the small G-protein, Ras, which in turn activates MKK6, resulting in activation of p38 MAPK [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] McDermott, 2002, Ras Participates in the Activation of p38 MAPK by Interleukin-1 by Associating with IRAK, IRAK2, TRAF6, and TAK-1, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BV-2 microglia treated with advanced oxidation protein products displayed increased NOX4 expression and elevated ROS, along with p38 MAPK and JNK activation.

    “Moreover, BV-2 microglia treated with advanced oxidation protein products, a hallmark of oxidative stress, displayed increased NOX4 expression and elevated ROS, along with p38 MAPK and JNK activation [155].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Liu, 2020, Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury, J. Neuroinflamm. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Lipid droplets are an important element of the redox response in microglia and are associated with AD-risk genes and neuronal death.

    “This evidence shows that lipid droplets are an important element of the redox response in microglia and these organelles are associated with AD-risk genes and neuronal death.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source

      Not checked in the free run.

    • cites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source

      Not checked in the free run.

    • cites [164] Liu, 2017, The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Specific pharmacological suppression of mROS by mitoTEMPO in LPS-stimulated primary murine microglia resulted in reduced activation of all three MAPKs and limited NFκB nuclear translocation, along with reduced expression of pro-inflammatory factors (TNFα, IL1β, IL6, iNOS and Cox-2).

    “Specific pharmacological suppression of mROS by mitoTEMPO in LPS-stimulated primary murine microglia resulted in reduced activation of all three MAPKs and limited NFκB nuclear translocation, along with the reduced expression of a battery of pro-inflammatory factors (TNFα, IL1β, IL6, iNOS and Cox-2) [158].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Park, 2015, Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways, Neurosci. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ethanol-related neurodegeneration is associated with increased microglial NFκB activation and gp91phox expression.

    “Ethanol-related neurodegeneration is associated with increased microglial NFκB activation and gp91phox expression [150].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Qin, 2012, NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration, J. Neuroinflamm. source

      Not checked in the free run.

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

    Premisenone given

    The MAPK family comprises three subgroups of serine/threonine kinases activated in response to a range of cellular signals, including proinflammatory cytokines, environmental stress and growth factors.

    “The mitogen-activated protein kinase (MAPK) family comprises three subgroups of serine/threonine kinases activated in response to a range of cellular signals, including proinflammatory cytokines, environmental stress and growth factors.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Lipid droplets are organelles formed in the endoplasmic reticulum, comprising a neutral lipid core encapsulated by a phospholipid monolayer, thought to function as a store of energy.

    “Lipid droplets (LD) are organelles formed in the endoplasmic reticulum, comprising of a neutral lipid (triacylglycerol and cholesteryl ester) core encapsulated by a phospholipid monolayer, thought to function as a store of energy [160].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Jackson, 2019, Lipid droplet biogenesis, Curr. Opin. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These findings were correlated with human post-mortem brain samples from alcoholic patients, yet the effect of NOX inhibition on NFκB activation in humans was not noted.

    “Critically, these findings were correlated with human post-mortem brain samples from alcoholic patients, yet the effect of NOX inhibition on NFκB activation in humans was not noted [150].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Qin, 2012, NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration, J. Neuroinflamm. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antioxidant treatment or human SOD1 expression in flies reduces LD formation and attenuates neurodegeneration.

    “Antioxidant treatment or human superoxide dismutase 1 (SOD1) expression in flies reduces LD formation and attenuates neurodegeneration [163].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source

      Not checked in the free run.

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

    Premisecitation

    MAPKs exert their effects on cellular physiology via myriad effectors, including transcription factors and further kinases.

    “MAPKs themselves exert their effects on cellular physiology via myriad effectors, including transcription factors and further kinases [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Kaminska, 2009, MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target, Anat. Rec. source

      Not checked in the free run.

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

    Premisecitation

    MAPKs share a common chain of activation mediated by sequential, three-tiered phosphorylation of upstream kinases.

    “MAPKs share a common chain of activation mediated by sequential, three-tiered phosphorylation of upstream kinases, i.e., signal transduction is mediated by phosphorylation of a MAPK kinase kinase (MKKK), which in turn activates a MAPK kinase (MKK) which activates the MAPK.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Kaminska, 2009, MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target, Anat. Rec. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HO-1 inhibition of NOX2 was mediated by both a reduction in heme availability and biliverdin and carbon monoxide, by-products of heme metabolism by HO-1 which may facilitate attenuation of TLR4 signalling by NOX inhibition.

    “This was mediated by both a reduction in heme availability and biliverdin and carbon monoxide, by-products of heme metabolism by HO-1 which may facilitate attenuation of TLR4 signalling by NOX inhibition [173,174].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [173] Nakahira, 2006, Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts, J. Exp. Med. source

      Not checked in the free run.

    • cites [174] Lanone, 2004, Induction of heme oxygenase-1 inhibits NAD(P)H oxidase activity by down-regulating cytochrome b558 expression via the reduction of heme availability, J. Biol. Chem. source

      Not checked in the free run.

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

    Premisecitation

    NCOA7 is induced in epithelial cells in response to rhinovirus infection and LPS-stimulated macrophages.

    “Furthermore, NCOA7 is induced in epithelial cells in response to rhinovirus infection and LPS-stimulated macrophages, the peripheral myeloid cousins of microglia [186,187].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [186] Baines, 2013, Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD, Respir. Res. source

      Not checked in the free run.

    • cites [187] Alasoo, 2015, Transcriptional profiling of macrophages derived from monocytes and iPS cells identifies a conserved response to LPS and novel alternative transcription, Sci. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of OXR1 results in pronounced microgliosis whilst neuronal OXR1 overexpression delays inflammation, indicating OXR1 regulation of microglial activation in a non-cell-autonomous fashion.

    “Loss of OXR1 results in pronounced microgliosis whilst neuronal OXR1 overexpression delays inflammation, indicating OXR1 regulation of microglial activation in a non-cell-autonomous fashion [184].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Liu, 2015, Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis, Brain source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Expression of these proteins by Nrf2 in microglia may represent a pathway that can be modulated to enhance innate defences and combat oxidative stress.

    “Expression of these proteins by Nrf2 in microglia may represent a pathway that can be modulated to enhance innate defences and combat oxidative stress.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    The function of these redox regulators in microglia is unclear as of yet.

    “The function of these redox regulators in microglia is unclear as of yet, however, many of these proteins are linked to inflammation, suggesting functionality in microglia.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Many antioxidant proteins function in the CNS, including classical antioxidants (superoxide dismutase, glutathione reductase, catalase, etc.) and TLDc proteins.

    “Many antioxidant proteins are understood to function in the CNS, including classical antioxidants (superoxide dismutase, glutathione reductase, catalase, etc. reviewed in [38]) and more recently TBC, LysM, domain catalytic (TLDc) proteins (oxidation resistance 1, nuclear receptor coactivator 7, Tbc1d24, etc. reviewed in [166]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Salim, 2017, Oxidative Stress and the Central Nervous System, J. Pharmacol. Exp. Ther. source

      Not checked in the free run.

    • cites [166] Finelli, 2017, TLDc proteins: New players in the oxidative stress response and neurological disease, Mamm. Genome source

      Not checked in the free run.

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

    Interpretationcitation

    ROS interaction with glia to elicit an immune response may involve reciprocal regulation between NOX2 and NFκB.

    “The two are undoubtedly linked; however, it is not clear how ROS interact with glia to elicit an immune response, although this may involve reciprocal regulation between NOX2 and NFκB [147].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Li, H., Luo, Y.-F., Wang, Y.-S., Yang, Q., Xiao, Y.-L., Cai, H.-R., and Xie, C.-M. (2020, June 16). Using ROS as a Second Messenger, NADPH Oxidase 2 Mediates Macrophage Senescence via Interaction with NF-κB during Pseudomonas aeruginosa Infection. Available online: https://www.hindawi.com/journals/omcl/2018/9741838/. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intracranial injection of sulforaphane enhanced Nrf2 levels which limited expression of pro-inflammatory microglial markers and conferred neuroprotection.

    “Intracranial injection of the isothiocyanate, sulforaphane, enhanced Nrf2 levels which limited expression of pro-inflammatory microglial markers and conferred neuroprotection [168,169,170].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [168] Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol. Baltim. source

      Not checked in the free run.

    • cites [169] Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease, Glia source

      Not checked in the free run.

    • cites [170] Jazwa, 2011, Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism, Antioxid. Redox Signal. source

      Not checked in the free run.

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

    Interpretationnone given

    LDAM are important regulators of oxidative stress and a mechanism by which protective inflammation may become dysregulated and damaging in ageing and neurodegeneration.

    “Finally, LDAM are important regulators of oxidative stress and a mechanism by which protective inflammation may become dysregulated and damaging in ageing and neurodegeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This signature involved the downregulation of microglial homeostatic genes (Tmem119, Cx3cr1) and overexpression of ROS-related genes Cybb (p91phox), Cyba (p22phox) and Nos2 (nitric oxide synthase 2); and pro-inflammatory genes Il1b, Cd47 and Prkcd (protein kinase C-δ).

    “This signature involved the downregulation of microglial homeostatic genes (Tmem119, Cx3cr1) and overexpression of ROS-related genes Cybb (p91phox), Cyba (p22phox) and Nos2 (nitric oxide synthase 2); and pro-inflammatory genes Il1b, Cd47 and Prkcd (protein kinase C-δ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The mechanism of LD accumulation in response to elevated ROS in flies and the perturbation of this mechanism by ApoeE-ε4 indicates LDAM are protective, potentially by sequestering peroxidised lipids.

    “The mechanism of LD accumulation in response to elevated ROS in flies and the perturbation of this mechanism by ApoeE-ε4 indicates LDAM are protective, potentially by sequestering peroxidised lipids [163,164].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source

      Not checked in the free run.

    • cites [164] Liu, 2017, The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D, Cell Metab. source

      Not checked in the free run.

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

    Interpretationreasoning

    Many of these redox regulators are linked to inflammation, suggesting functionality in microglia.

    “The function of these redox regulators in microglia is unclear as of yet, however, many of these proteins are linked to inflammation, suggesting functionality in microglia.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    It is feasible that ROS act as secondary messengers in microglia to propagate inflammatory states and may contribute to immune dysregulation, leading to persistent and inappropriate inflammation.

    “However, it is feasible that ROS act as secondary messengers in microglia to propagate inflammatory states and may contribute to immune dysregulation, leading to persistent and inappropriate inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    LDAM are dysfunctional in neurodegeneration, where they may be unable to clear aggregated protein but would induce oxidative stress and inflammatory cascades.

    “This implies LDAM are dysfunctional in neurodegeneration, where they may be unable to clear aggregated protein but would induce oxidative stress and inflammatory cascades.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source

      Not checked in the free run.

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

    Interpretationnone given

    Molecular pathways in microglia contributing to neurodegeneration undoubtedly involve inflammatory-mediated ROS production by activation of NOX.

    “Molecular pathways in microglia contributing to neurodegeneration undoubtedly involve inflammatory-mediated ROS production by activation of NOX.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In microglia, Nrf2-deficiency promotes inflammatory marker expression (IL6, Cox2, iNOS) whilst inhibiting anti-inflammatory marker expression (arginase 1, IL4) in response to LPS and MPTP.

    “In microglia, Nrf2-deficiency promotes inflammatory marker expression (IL6, Cox2, iNOS) whilst inhibiting anti-inflammatory marker expression (arginase 1, IL4) in response to LPS and MPTP [168,169].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [168] Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol. Baltim. source

      Not checked in the free run.

    • cites [169] Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease, Glia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Specific disruption of the OXR1 TLDc domain in mice is sufficient to cause neurodegeneration and loss-of-function polymorphisms in human TLDc proteins result in a neurodegenerative phenotype.

    “The mechanism by which TLDc proteins confer stress resistance is unclear, however, specific disruption of the OXR1 TLDc domain in mice is sufficient to cause neurodegeneration and loss-of-function polymorphisms in human TLDc proteins result in a neurodegenerative phenotype [182,183].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [182] Finelli, 2016, The Evolutionarily Conserved Tre2/Bub2/Cdc16 (TBC), Lysin Motif (LysM), Domain Catalytic (TLDc) Domain Is Neuroprotective against Oxidative Stress, J. Biol. Chem. source

      Not checked in the free run.

    • cites [183] Wang, 2019, Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction, Am. J. Hum. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A unique, short-isoform of NCOA7, NCOA7-B or NCOA7-AS, is strongly linked to inflammatory activation, especially by viral-related stimuli such as interferons (IFNs), and functional inhibition of endosome-mediated viral-entry by NCOA7-B has been demonstrated.

    “Finally, a unique, short-isoform of NCOA7, NCOA7-B or NCOA7-AS, is strongly linked to inflammatory activation, especially by viral-related stimuli such as interferons (IFNs), and functional inhibition of endosome-mediated viral-entry by NCOA7-B has been demonstrated [185].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] Doyle, 2018, The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry, Nat. Microbiol. source

      Not checked in the free run.

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

    Interpretationnone given

    It is unlikely ROS are the primary trigger of inflammation in Alzheimer's disease; this is likely mediated by DAMPs associated with toxic protein aggregation.

    “It is unlikely ROS are the primary trigger of inflammation in Alzheimer’s disease; this is likely mediated by DAMPs associated with toxic protein aggregation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LDAM are also ROS-generating and pro-inflammatory yet defective in phagocytosis in murine models.

    “However, LDAM are also ROS-generating and pro-inflammatory yet defective in phagocytosis in murine models [162].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Microgliosis and sulforaphane neuroprotection were attenuated in Nrf2-deficient mice, which confirms a mechanistic link between Nrf2 and immune regulation.

    “Microgliosis and sulforaphane neuroprotection were attenuated in Nrf2-deficient mice which confirms a mechanistic link between Nrf2 and immune regulation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [168] Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol. Baltim. source

      Not checked in the free run.

    • cites [169] Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease, Glia source

      Not checked in the free run.

    • cites [170] Jazwa, 2011, Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism, Antioxid. Redox Signal. source

      Not checked in the free run.

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

    Premisecitation

    The expression of this short-isoform in ovarian follicles is regulated intracellularly by MAPKs, p38 and ERK, which are recognised mediators of the pro-inflammatory response in microglia.

    “Furthermore, the expression of this short-isoform in ovarian follicles is regulated intracellularly by MAPKs, p38 and ERK, which are recognised mediators of the pro-inflammatory response in microglia [191].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191] Shkolnik, 2008, Molecular characterization and bioinformatics analysis of Ncoa7B, a novel ovulation-associated and reproduction system-specific Ncoa7 isoform, Reproduction source

      Not checked in the free run.

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

    Interpretationreasoning

    The concerted kinase activity of MAPKs and PKC may create a strong pro-oxidant signal by vigorous and persistent phosphorylation of both each other's activation pathways and NOX2 regulatory subunits, resulting in enhanced and sustained ROS production.

    “For example, the concerted kinase activity of MAPKs and PKC may create a strong pro-oxidant signal by vigorous and persistent phosphorylation of both each other’s activation pathways and NOX2 regulatory subunits, resulting in enhanced and sustained ROS production.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Many experiments examining the role of quinone-related compounds have been conducted in immortalised microglia, e.g., BV2 cells.

    “Notably, many experiments examining the role have been conducted in immortalised microglia, e.g., BV2 cells.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    A vicious cycle likely exists in which neuroinflammatory signals induce ROS release, which then promotes further deleterious inflammation.

    “This likely involves a vicious cycle in which neuroinflammatory signals induce ROS release, which then promotes further deleterious inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gene network analysis identified upregulation of glutathione transferase activity in ROS-generating microglia, which was rescued by acivin, a compound which inhibits glutathione degradation.

    “Gene network analysis identified upregulation of glutathione transferase activity in ROS-generating microglia, which was rescued by acivin, a compound which inhibits glutathione degradation [181].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The authors were able to characterise the molecular mechanism of acivin, as well as demonstrate improved functional outcomes in a mammalian model of neurodegeneration.

    “The authors were able to characterise the molecular mechanism of acivin, as well as demonstrate improved functional outcome’s in a mammalian model of neurodegeneration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acivin effectively reduced oxidative stress and neuronal death in the EAE model without toxicity to other CNS cell types.

    “Acivin effectively reduced oxidative stress and neuronal death in the EAE model without toxicity to other CNS cell types.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source

      Not checked in the free run.

79 of 79

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?

  • Treatment options for neuroinflammation associated with AD have been investigated, including IL-1β antagonists such as canakinumab.

    “Treatment options for neuroinflammation associated with AD have been investigated, including IL-1β antagonists such as canakinumab [206,207,208].”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [207]

  • Research on cytokine inhibition has focused on anti-inflammatory medications that interact with pro-inflammatory cytokines such as TNF-a and IL-1 beta.

    “Research on cytokine inhibition has focused on anti-inflammatory medications that interact with pro-inflammatory cytokines such as TNF-a and IL-1 beta.”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [207]

Cites

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4 of the 198 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. 2018, Epidemiology of Alzheimer’s disease and other dementias, Rev. Neurol., 66, 377

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Authors
Simpson, D. S. A., & Oliver, P. L.
Affiliations
University of Oxford (GB)
Corresponding author
Oliver, Peter L.
ORCID
Venue
Antioxidants
Publisher
MDPI AG
Published
2020-08-13
Volume
9
Issue
8
Pages
743
ISSN
2076-3921 (ISSN-L)
DOI
10.3390/antiox9080743
PMC
PMC7463655
OpenAlex
W3048426432
Cited by
1,044
References
198
Citations by year
2026: 156 · 2025: 249 · 2024: 201 · 2023: 183 · 2022: 133 · 2021: 113 · 2020: 9
FWCI
10.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Antioxidants (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Medical Research Council (MR/P502005/1)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
reactive oxygen species, microglia, neuroinflammation, oxidative stress, neurodegenerative diseases, Alzheimer's disease, NADPH oxidase 2, NOX2, damage-associated molecular patterns, disease-associated microglia, mitochondrial reactive oxygen species, NQO1, Nrf2, amyloid plaques, antioxidant therapeutics, anti-inflammatory agents

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 2026-10-10.

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

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