The DOI matches its Crossref record; 194 of the 198 references it cites were found in a registry or an index; 2 of the 222 sources its claims cite were checked for support.
ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease
Open accessAbstract
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.
Overview
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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.
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Figures
![Figure 1 NADPH oxidase 2 (NOX2) is activated by translocation of cytosolic subunits to the membrane. gp91phox and p22phox are membrane-bound components of NOX2 that together form the flavocytochrome b558. Upon activation signalling by pro-inflammatory stimuli, e.g., interferon-γ, protein kinases activate the cytosolic regulatory subunits: p40phox, p47phox and p67phox. Phosphorylation of p47phox by p21-activated kinase is thought to be the rate-limiting step in NOX2 activation [62]. The small GTPase Rac1/2 is also activated and translocated to the flavocytochrome. Upon activation, NOX2 catalyses the production of the superoxide radical (O2•–) from molecular oxygen (O2) by oxidation of nicotinamide adenine dinucleotide phosphate (NADPH) to form NADP+ and H+.](/paper-figures/68b11a4660b94e749a9fded2b95a611b/ros-generation-in-microglia-understanding-oxidative-stress-and-inflammation-in-figure-1.jpg)
Verification
Claims the paper makes
133 Not checked yet · 37 Own interpretation · 8 No basis given · 1 Mixed support · accuracy not yet measured
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In the paper
“Multiple studies have shown that H2O2-mediated NFκB activation results from phosphorylation of IκB tyrosine residues [143,144].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Disputedcites [143] Schoonbroodt, 2000, Crucial Role of the Amino-Terminal Tyrosine Residue 42 and the Carboxyl-Terminal PEST Domain of IκBα in NF-κB Activation by an Oxidative Stress, J. Immunol. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says H₂O₂-induced NF-κB activation probably relies on an unmodified IκBα tyrosine 42 and phosphorylation of the carboxyl-terminal PEST sequence. The paper finds tyrosine 42 necessary for activation, but does not identify phosphorylation of tyrosine residues as its cause; its proposed mechanism points elsewhere. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Supportedcites [144] Takada, 2003, Hydrogen Peroxide Activates NF-κB through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of p65 evidence for the involvement of IκBα kinase and Syk protein-tyrosine kinase, J. Biol. Chem. source
The Discussion states that H₂O₂ induces tyrosine phosphorylation of IκBα and that Syk-dependent phosphorylation is critical for NF-κB activation. The paper’s summary likewise identifies Syk-mediated tyrosine phosphorylation of IκBα as the activation mechanism. (LLM, conf=0.94)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Disputed
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Critically, this identifies a mechanistic link between microglial activation in AD and the development of tau pathology.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.2. Microglial Activation and Oxidative Stress Are Hallmarks of Neurodegenerative Disease
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 2. Inflammatory-Related ROS Production—NOX Mediates Production of ROS in Microglia > 2.1. NOX Are a Family of Enzyme Subunits that Mediate Deliberate Production of ROS in Inflammation
What the sources say
- Not checked yetcites [45] Nathan, 1986, Secretion of toxic oxygen products by macrophages: Regulatory cytokines and their effects on the oxidase, Ciba Found. Symp.
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“thus intracellular ROS signalling may underlie excessive inflammation and OS.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“since there is a strong correlation between immune activation and oxidative damage in neurodegenerative disease [42,43,44]”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.3. The Brain Is Especially Susceptible to Oxidative Stress
What the sources say
- Not checked yetcites [42] Heneka, 2015, Neuroinflammation in Alzheimer’s disease, Lancet Neurol. source
- Not checked yetcites [43] Trushina, 2017, Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease, J. Alzheimers Dis. JAD source
- Not checked yetcites [44] Reiss, 2018, Amyloid toxicity in Alzheimer’s disease, Rev. Neurosci. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“microglial ROS likely contribute to oxidative stress associated with neurodegeneration.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.2. Microglial Activation and Oxidative Stress Are Hallmarks of Neurodegenerative Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > Abstract
What the sources say
- Not checked yetcites [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 yetcites [28] Klegeris, 1997, beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate, J. Neurosci. Res. source
- Not checked yetcites [29] Schilling, 2011, Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia, J. Cell. Physiol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Immune involvement in neurodegenerative disease centres on findings that pro-inflammatory microglia are closely associated with protein aggregate pathologies characteristic of most dementias.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.2. Microglial Activation and Oxidative Stress Are Hallmarks of Neurodegenerative Disease
What the sources say
- Not checked yetcites [12] Mielke, 2011, Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease, Am. J. Pathol. source
- Not checked yetcites [13] Hickman, 2008, Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer’s Disease Mice, J. Neurosci. source
- Not checked yetcites [14] Zhao, 2017, Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease, Mol. Neurodegener. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Further, activated microglia promote tau phosphorylation and aggregation by activation of the NLRP3 (nucleotide binding oligomerisation domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3) inflammasome in response to amyloid-β [22,23].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.2. Microglial Activation and Oxidative Stress Are Hallmarks of Neurodegenerative Disease
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The brain is particularly susceptible to oxidative stress due to a triad of elevated ROS production, modest antioxidant defences and a limited capacity for regeneration [39].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.3. The Brain Is Especially Susceptible to Oxidative Stress
What the sources say
- Not checked yetcites [39] Cobley, 2018, 13 reasons why the brain is susceptible to oxidative stress, Redox Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As phagocytes, microglia are capable of mediating an “oxidative/respiratory burst” in response to pathogen- and damage-AMPs, including aggregated protein and cellular debris [40,41].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.3. The Brain Is Especially Susceptible to Oxidative Stress
What the sources say
- Not checked yetcites [40] Claude, 2013, Microglial CD33-related Siglec-E inhibits neurotoxicity by preventing the phagocytosis-associated oxidative burst, J. Neurosci. Off. J. Soc. Neurosci. source
- Not checked yetcites [41] Herzog, C., Pons Garcia, L., Keatinge, M., Greenald, D., Moritz, C., Peri, F., and Herrgen, L. (2019). Rapid clearance of cellular debris by microglia limits secondary neuronal cell death after brain injury in vivo. Dev. Camb. Engl., 146. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2)”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > Abstract
What the sources say
- Not checked yetcites [72] Zhang, 2014, An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex, J. Neurosci. source
- Not checked yetcites [73] Zhang, 2016, Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse, Neuron source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Neuronal damage is an important triggering factor for NOX activation in microglia, likely mediated by DAMPs originating from neurones in both acute injury and chronic neuroinflammation [89,90].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.2. Damage-Associated Molecular Patterns (DAMPs) Originating from Neurons Mediate NOX Activation via Pattern Recognition Receptors CR3 and TLR4
What the sources say
- Not checked yetcites [89] Gülke, E., Gelderblom, M., and Magnus, T. (2018). Danger signals in stroke and their role on microglia activation after ischemia. Ther. Adv. Neurol. Disord., 11. source
- Not checked yetcites [90] Rubartelli, A. (2014). DAMP-Mediated Activation of NLRP3-Inflammasome in Brain Sterile Inflammation: The Fine Line between Healing and Neurodegeneration. Front. Immunol., 5. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In situ hybridisation has demonstrated upregulated and persistent cortical NOX4 expression in response to cerebral ischaemia [75]”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
What the sources say
- Not checked yetcites [75] Vallet, 2005, Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia, Neuroscience source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“CR3 stimulation results in extracellular signal-regulated kinase (ERK)-stimulated translocation of p47phox to the plasma membrane indicating NOX2 activation [86].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.1. NOX2 and NOX4 Are Activated by Acute, Pro-Inflammatory Stimulation of Microglia
What the sources say
- Not checked yetcites [86] Hou, 2018, Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway, Redox Biol. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This indicates that NOX2 involvement in neuroinflammation may be associated with Parkinson’s disease.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.1. NOX2 and NOX4 Are Activated by Acute, Pro-Inflammatory Stimulation of Microglia
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Robust and constitutive expression of NOX in microglia has been demonstrated and is the focus of this section.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia
What the sources say
- Not checked yetcites [72] Zhang, 2014, An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex, J. Neurosci. source
- Not checked yetcites [73] Zhang, 2016, Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse, Neuron source
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“Genetic deletion or pharmacological inhibition of NOX2 in a mouse model of traumatic brain injury (TBI) demonstrates attenuation of pro-inflammatory microglial phenotype, indicated by reduced expression of cytokines, including IL1β, IL6 and TNFα, 1-day post-injury [88].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.1. NOX2 and NOX4 Are Activated by Acute, Pro-Inflammatory Stimulation of Microglia
What the sources say
- Not checked yetcites [88] Kumar, 2016, NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury, Brain. Behav. Immun. source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“DAMP stimulation of PRRs on microglia, such as CR3 and toll-like receptor 4 (TLR4), mediates activation of pro-inflammatory signalling transducers NLRP3 inflammasome, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and mitogen-activated protein kinases (MAPKs), such as ERK [86,91,92].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.2. Damage-Associated Molecular Patterns (DAMPs) Originating from Neurons Mediate NOX Activation via Pattern Recognition Receptors CR3 and TLR4
What the sources say
- Not checked yetcites [86] Hou, 2018, Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway, Redox Biol. source
- Not checked yetcites [91] Savage, C.D., Lopez-Castejon, G., Denes, A., and Brough, D. (2012). NLRP3-Inflammasome Activating DAMPs Stimulate an Inflammatory Response in Glia in the Absence of Priming Which Contributes to Brain Inflammation after Injury. Front. Immunol., 3. source
- Not checked yetcites [92] Kawai, 2011, Toll-like receptors and their crosstalk with other innate receptors in infection and immunity, Immunity source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“single-cell (sc)RNA-seq has determined that NOX2 (CYBB) is the most highly expressed NOX isotype transcript in human and mouse brain microglia, concurrent with expression in peripheral macrophages [71,72,73].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
What the sources say
- Not checked yetcites [71] Nauseef, 2008, Biological Roles for the NOX Family NADPH Oxidases, J. Biol. Chem. source
- Not checked yetcites [72] Zhang, 2014, An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex, J. Neurosci. source
- Not checked yetcites [73] Zhang, 2016, Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse, Neuron source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“NOX1 expression may be an artefact of the Cx3cr1-EGFP reporter line, since Cx3cr1 is a signature microglial gene and haploinsufficiency has wide-reaching effects on gene expression of microglia, specifically encouraging a prematurely aged transcriptome [78,79,80].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
What the sources say
- Not checked yetcites [78] Gyoneva, S., Hosur, R., Gosselin, D., Zhang, B., Ouyang, Z., Cotleur, A.C., Peterson, M., Allaire, N., Challa, R., and Cullen, P. (2019). Cx3cr1-deficient microglia exhibit a premature aging transcriptome. Life Sci. Alliance, 2. source
- Not checked yetcites [79] Hickman, S.E., Allison, E.K., Coleman, U., Kingery-Gallagher, N.D., and El Khoury, J. (2019). Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer’s Like-Disease in PS1-APP Mice. Front. Immunol., 10. source
- Not checked yetcites [80] Lee, 2010, CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer’s Disease Mouse Models, Am. J. Pathol. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“NOX2 activity in dopaminergic neurodegeneration is mediated by activation of complement receptor 3 (CR3, aka macrophage-1 antigen (MAC1)), which is a pattern recognition receptor (PRR) comprised of CD11b and CD18 and agonised by DAMPs which contributes to phagocytic activation in response to aggregated protein [85,86].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.1. NOX2 and NOX4 Are Activated by Acute, Pro-Inflammatory Stimulation of Microglia
What the sources say
- Not checked yetcites [85] Fu, 2012, Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia, Glia source
- Not checked yetcites [86] Hou, 2018, Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway, Redox Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“NOX4 has the second-highest transcript expression in microglia, albeit at a much lower level [72,73].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
What the sources say
- Not checked yetcites [72] Zhang, 2014, An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex, J. Neurosci. source
- Not checked yetcites [73] Zhang, 2016, Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse, Neuron source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, the activity of phagocytic NOX is regulated by the membrane translocation of these cytosolic subunits.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 2. Inflammatory-Related ROS Production—NOX Mediates Production of ROS in Microglia > 2.3. Phagocytic NOX (NOX1-3) Are Regulated by the Assembly of Cytosolic Subunits
What the sources say
- Not checked yetcites [61] Diebold, 2001, Molecular basis for Rac2 regulation of phagocyte NADPH oxidase, Nat. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the maximum capacity of microglia to produce ROS will be determined, at least in part, by the expression level of NOX isoforms.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“Primary midbrain cultures from NOX2 knockout rats are more resistant to neurotoxicity by synergistic treatment with lipopolysaccharide (LPS) and α-synuclein [84].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.1. NOX2 and NOX4 Are Activated by Acute, Pro-Inflammatory Stimulation of Microglia
What the sources say
- Not checked yetcites [84] Zhang, 2018, Minimally Toxic Dose of Lipopolysaccharide and α-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation, Mol. Neurobiol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The robust activation of NOX isoforms in response to acute neuronal injury and chronic inflammation with oxidative damage has been well documented in post-mortem tissue and models of neurodegeneration (reviewed in [83]).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.1. NOX2 and NOX4 Are Activated by Acute, Pro-Inflammatory Stimulation of Microglia
What the sources say
- Not checked yetcites [83] Ma, 2017, NADPH oxidase in brain injury and neurodegenerative disorders, Mol. Neurodegener. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Furthermore, fibrinogen, a DAMP which is closely associated with cerebral amyloid angiopathy (CAA), induces ROS production by NOX2 in microglia via stimulation of CR3 [104].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.2. Damage-Associated Molecular Patterns (DAMPs) Originating from Neurons Mediate NOX Activation via Pattern Recognition Receptors CR3 and TLR4
What the sources say
- Not checked yetcites [104] Merlini, 2019, Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model, Neuron source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Since these pathways converge on pro-inflammatory signalling in DAM, NOX2 activation may be an important pro-inflammatory mechanism in microglia.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 2. Inflammatory-Related ROS Production—NOX Mediates Production of ROS in Microglia > 2.3. Phagocytic NOX (NOX1-3) Are Regulated by the Assembly of Cytosolic Subunits
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Both in co-culture and in vivo, toxins associated with neurodegeneration, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), LPS and diesel exhaust particles, cause CR3 stimulation by the DAMP, high mobility group box 1 (HMGB1), which results in activation of NOX2 and production of O2•– [101,102,103].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.2. Damage-Associated Molecular Patterns (DAMPs) Originating from Neurons Mediate NOX Activation via Pattern Recognition Receptors CR3 and TLR4
What the sources say
- Not checked yetcites [101] Gao, 2011, HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration, J. Neurosci. Off. J. Soc. Neurosci. source
- Not checked yetcites [102] Levesque, 2013, The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function, J. Neurochem. source
- Not checked yetcites [103] Pei, 2007, MAC1 mediates LPS-induced production of superoxide by microglia: The role of pattern recognition receptors in dopaminergic neurotoxicity, Glia source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unsurprisingly, the classical phagocytic NOX, NOX2, plays a key role in inflammatory-mediated ROS production in microglia.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.1. NOX2 and NOX4 Are Activated by Acute, Pro-Inflammatory Stimulation of Microglia
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests greater availability of cytosolic regulatory subunits contributes to excessive NOX2 activation in AD.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Additionally, human CAA post-mortem capillaries with amyloid-β load are surrounded by NOX2-positive microglia [122,123].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [122] Carrano, 2011, Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy, Antioxid. Redox Signal. source
- Not checked yetcites [123] Carrano, 2012, Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy, Neurodegener. Dis. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Tau aggregates in neuronal-astrocytic co-cultures stimulate NOX activity and ROS production leading to neuronal death [127].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [127] Esteras, N., Kundel, F., Amodeo, G.F., Pavlov, E.V., Klenerman, D., and Abramov, A.Y. (2020). Insoluble tau aggregates induce neuronal death through modification of membrane ion conductance, activation of voltage-gated calcium channels and NADPH oxidase. FEBS J. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that the NOX response to tau may be, at least in part, localised to astrocytes or neurones.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these findings strongly suggest a specific role for NOX2 activation in microglia associated with cerebral amyloid pathology.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Since TLR4 signalling mediates the macrophage and microglial LPS response, which includes MAPK activation, it is suggested that H2O2 acts downstream of TLR4 signalling, specifically to activate NFκB signalling.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“At physiological concentrations, ROS are vital secondary messengers in multiple cellular processes, including inflammation, cellular growth and differentiation [136,137].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia
What the sources say
- Not checked yetcites [136] Zhang, J., Wang, X., Vikash, V., Ye, Q., Wu, D., Liu, Y., and Dong, W. (2020, May 02). ROS and ROS-Mediated Cellular Signaling. Available online: https://www.hindawi.com/journals/omcl/2016/4350965/. source
- Not checked yetcites [137] Murphy, 2011, Unraveling the Biological Roles of Reactive Oxygen Species, Cell Metab. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [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 yetcites [139] Zheng, 2011, Structural studies of NF-κB signaling, Cell Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Crucially, these data highlight that NOX activation is related to amyloidosis even when mutant human amyloid-processing proteins are expressed at endogenous levels.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Further, there is evidence tauopathy is driven by NLRP3 inflammasome activation in microglia in response to amyloid-β [23].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [23] Ising, 2019, NLRP3 inflammasome activation drives tau pathology, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, elevated NOX activity and expression in DAM plays a critical role in neuronal loss seen in AD as a result of neuroinflammatory responses to amyloid-β, especially related to the cerebrovasculature.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Exogenous application of H2O2 or induction of H2O2 release by IL1β or LPS treatment can activate NFκB in multiple cell types, including human myeloid KBM-5 cells, human epithelial-like MCF-7 cells, mouse EL-5 T-cells and macrophages [143,144,145,146].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [143] Schoonbroodt, 2000, Crucial Role of the Amino-Terminal Tyrosine Residue 42 and the Carboxyl-Terminal PEST Domain of IκBα in NF-κB Activation by an Oxidative Stress, J. Immunol. source
- Not checked yetcites [144] Takada, 2003, Hydrogen Peroxide Activates NF-κB through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of p65 evidence for the involvement of IκBα kinase and Syk protein-tyrosine kinase, J. Biol. Chem. source
- Not checked yetcites [145] Li, 2006, Interleukin-1β Induction of NFκB Is Partially Regulated by H2O2-mediated Activation of NFκB-inducing Kinase, J. Biol. Chem. source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) is a master transcription factor controlling pro-inflammatory gene expression in microglia.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [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 yetcites [139] Zheng, 2011, Structural studies of NF-κB signaling, Cell Res. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Further, NFκB may reciprocally regulate NOX2 expression, since its downregulation suppresses gp91phox in the same model.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The localisation of isoform activity in the AD brain is unknown, however, NOX2 is highly expressed in microglia [72], therefore it is likely microglial NOX activation accounts for at least part of AD-related NOX activity.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [72] Zhang, 2014, An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex, J. Neurosci. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Activation of NFκB by inflammatory stimuli is mediated by phosphorylation and ubiquitin-mediated degradation of IκB which disinhibits NFκB, allowing for nuclear translocation to target genes and activation of transcription [140].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [140] Dresselhaus, E.C., and Meffert, M.K. (2019). Cellular Specificity of NF-κB Function in the Nervous System. Front. Immunol., 10. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Inhibiting NOX with the naturally occurring compound, apocynin, or genetic deletion of gp91phox in mice (Tg2576) overexpressing mutant amyloid precursor protein (APP), attenuates cerebral amyloid angiopathy (CAA) [115,116].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [115] Han, 2015, Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice, Proc. Natl. Acad. Sci. USA source
- Not checked yetcites [116] Park, 2005, NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide, J. Neurosci. Off. J. Soc. Neurosci. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests a functional specificity of NOX2 in microglia.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“However, this process does not involve the degradation of IκB, which is controlled by IκB kinase (IKK)-mediated serine phosphorylation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [143] Schoonbroodt, 2000, Crucial Role of the Amino-Terminal Tyrosine Residue 42 and the Carboxyl-Terminal PEST Domain of IκBα in NF-κB Activation by an Oxidative Stress, J. Immunol. source
- Not checked yetcites [144] Takada, 2003, Hydrogen Peroxide Activates NF-κB through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of p65 evidence for the involvement of IκBα kinase and Syk protein-tyrosine kinase, J. Biol. Chem. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Whilst overexpression of gp91phox increased NFκB activation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“H2O2-mediated activation is, instead, regulated by activation of spleen tyrosine kinase (Syk) [144].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [144] Takada, 2003, Hydrogen Peroxide Activates NF-κB through Tyrosine Phosphorylation of IκBα and Serine Phosphorylation of p65 evidence for the involvement of IκBα kinase and Syk protein-tyrosine kinase, J. Biol. Chem. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Furthermore, ante-mortem cognitive impairment is correlated with post-mortem determination of NOX activity in the frontal and temporal cortices [68].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [68] Ansari, 2011, NADPH-oxidase activation and cognition in Alzheimer disease progression, Free Radic. Biol. Med. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, NOX2 activation, along with elevated expression of NOX1 and NOX3, may be directly related to neuronal loss manifesting as cognitive decline in AD.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Multiple key signalling pathways contribute to microglial immune activation, including NFκB and MAPKs (Figure 3) and there is evidence ROS is an important modulator of the immune response by influencing these cell signalling pathways in microglia.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia
What the sources say
- Not checked yetcites [136] Zhang, J., Wang, X., Vikash, V., Ye, Q., Wu, D., Liu, Y., and Dong, W. (2020, May 02). ROS and ROS-Mediated Cellular Signaling. Available online: https://www.hindawi.com/journals/omcl/2016/4350965/. source
- Not checked yetcites [137] Murphy, 2011, Unraveling the Biological Roles of Reactive Oxygen Species, Cell Metab. source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“It is vital to determine pathways of persistent activation in microglia since this underpins the chronic inflammatory state in neurological diseases with an inflammatory aspect [151].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [151] Streit, 2004, Microglia and neuroinflammation: A pathological perspective, J. Neuroinflamm. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Progranulin (GRN) was determined to be a genetic regulator of LDAM formation and loss-of-function mutations in GRN are a cause of frontotemporal dementia [162,165].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Critically, ROS-stimulated microglial LD formation is mediated, in part, by apolipoproteins and transgenic human AD risk allele, ApoE-ε4, impairs LD formation a fly model [164].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
- Not checked yetcites [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
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Whilst the ROS generated here are believed to originate from NOX4 expression, the specificity of apocynin for NOX4 has been questioned [157].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [157] Wind, 2010, Comparative pharmacology of chemically distinct NADPH oxidase inhibitors, Br. J. Pharmacol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Oxidant production and inflammation are closely linked and it is imperative to properly determine the correct sequence of events since ROS production itself can result from inflammation and NFκB activation via iNOS expression and cytokine-activation of NOX2.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
In the paper
“In mouse and fly models of neurodegeneration, LD accumulation correlates with the onset of neuronal death, suggesting a crucial role for LDAM in neuronal loss [163].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
- Not checked yetcites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Critically, ROS-stimulated microglial LD formation is mediated, in part, by apolipoproteins and transgenic human AD risk allele, ApoE-ε4, impairs LD formation a fly model [164].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“ROS may contribute to microglial activation via p38 and JNK activation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [154] Yan, 2013, JNK and NADPH oxidase involved in fluoride-induced oxidative stress in BV-2 microglia cells, Mediat. Inflamm. source
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In microglia, lipid droplets form in response to innate inflammation, ageing and neurodegeneration and are mediated by canonical pathways of microglial activation, such as p38 MAPK [161,162].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease
What the sources say
- Not checked yetcites [161] Khatchadourian, 2012, Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia, Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids
- Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, the selectivity of mitoTEMPO as a mitochondrial-targeted antioxidant has been questioned, especially at higher concentrations [159].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [159] Bordt, 2014, NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: A bipartisan affair?, Free Radic. Biol. Med. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Attenuating fluoride-induced oxidative stress in BV-2 microglia with the antioxidant, melatonin, results in reduced JNK activation [154].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [154] Yan, 2013, JNK and NADPH oxidase involved in fluoride-induced oxidative stress in BV-2 microglia cells, Mediat. Inflamm. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Knockdown of NOX4 by RNAi reduced NLRP3 activation, suggesting a potential target to reduce NLRP3-stimulated pathology in neurodegenerative disease [155].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“It was determined that ROS elevation as a result of neuronal mitochondrial dysfunction and JNK activation drives LDAM formation in flies.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
- Not checked yetcites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Oxidant production and inflammation are closely linked and it is imperative to properly determine the correct sequence of events since ROS production itself can result from inflammation and NFκB activation via iNOS expression and cytokine-activation of NOX2.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“ROS from NOX4 also contribute to activation of the NLRP3 inflammasome, a driver of both amyloid-β [156] and tau [23] pathology.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Elevated O2•– and markers of neurodegeneration were reduced by pharmacological NOX inhibition.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [150] Qin, 2012, NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration, J. Neuroinflamm. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Mitochondrial ROS (mROS), independent of NOX-generated ROS, are also involved in the inflammatory response of microglia by activating MAPKs.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Thus, ROS originating from NOX4 activation may be important in activating microglia in response to neuronal damage via stimulation of p38 MAPK and JNK.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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 yetcites [157] Wind, 2010, Comparative pharmacology of chemically distinct NADPH oxidase inhibitors, Br. J. Pharmacol. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Therefore, MAPK and NFκB activation in microglial cells and the concurrent upregulation of pro-inflammatory mediators is facilitated, at least in part, by mROS.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Progranulin (GRN) was determined to be a genetic regulator of LDAM formation and loss-of-function mutations in GRN are a cause of frontotemporal dementia [162,165].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“ROS from NOX4 also contribute to activation of the NLRP3 inflammasome, a driver of both amyloid-β [156] and tau [23] pathology.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, the coincidence of ROS and NFκB activation in microglia is insufficient to determine a causal relationship.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Specifically, in microglia, LPS treatment results in the activation of mitogen-activated protein kinase kinase kinase 1 (MAP3K1, also known as MEKK1), which is an upstream activator of IKK [148].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [148] Delgado, 2002, Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia, Biochem. Biophys. Res. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“One such state that is strongly associated with oxidative stress and neurodegeneration are lipid droplet-accumulating microglia (LDAM).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease
What the sources say
- Not checked yetcites [10] Deczkowska, 2018, Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration, Cell source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In a model of spinal cord injury, apocynin, a NOX-inhibitor (see above), reduced activation of p38 MAPK and JNK and expression of TNFα and IL1β [155].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this sense, LDAM may underpin a positive feedback loop of stress-mediated ROS generation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.2. Lipid-Droplet Accumulating Microglia May Represent a Double-Edged Sword in Neurodegeneration
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further, LDs may be involved in dysregulation of microglial function.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The consequences of microglial ROS production on the parenchyma can become pathological, but the impetus for excessive ROS production in a pathological setting is unknown.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Antioxidant genes regulated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2) possess functional roles to limit microglial inflammation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
What the sources say
- Not checked yetcites [167] Itoh, 1997, An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements, Biochem. Biophys. Res. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Importantly, during the inflammatory response observed in models of neurodegeneration, many molecular mediators of inflammation are activated concurrently.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Single-cell RNAseq of ROS-positive microglia (ToxSeq) in an experimental autoimmune encephalomyelitis (EAE) model has identified a unique transcriptional signature in such stress-associated microglia [181].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.2. At the Forefront of Drug Discovery: ToxSeq Analysis of ROS-Generating Microglia
What the sources say
- Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“A striking (>60-fold) and robust induction of NCOA7-B occurs in peripheral blood mononuclear cells and macrophages treated with interferon-β-1b (IFNβ1b) or LPS.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.2. A Role for TLDc Proteins in Neuroinflammation
What the sources say
- Not checked yetcites [188] Zimmerer, 2008, Gene expression profiling reveals similarities between the in vitro and in vivo responses of immune effector cells to IFN-alpha, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. source
- Not checked yetcites [189] Honda, 2010, Differential interferon signaling in liver lobule and portal area cells under treatment for chronic hepatitis C, J. Hepatol. source
- Not checked yetcites [190] Yu, 2015, Induction of a Unique Isoform of the NCOA7 Oxidation Resistance Gene by Interferon β-1b, J. Interferon Cytokine Res. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“A plethora of plant-derived, quinone-related compounds have been demonstrated to limit microglial inflammation by activation of the Nrf2 pathway and subsequent upregulation of ARE-containing genes, including tiliroside, petatewalide B, emodin and β-lapachone, to name a few [176,177,178,179].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
What the sources say
- Not checked yetcites [176] Velagapudi, 2018, Activation of Nrf2 Pathway Contributes to Neuroprotection by the Dietary Flavonoid Tiliroside, Mol. Neurobiol. source
- Not checked yetcites [177] Park, 2018, AMPK/Nrf2 signaling is involved in the anti-neuroinflammatory action of Petatewalide B from Petasites japonicus against lipopolysaccharides in microglia, Immunopharmacol. Immunotoxicol. source
- Not checked yetcites [178] Park, 2016, Anti-neuroinflammatory Effect of Emodin in LPS-Stimulated Microglia: Involvement of AMPK/Nrf2 Activation, Neurochem. Res. source
- Not checked yetcites [179] Lee, 2015, β-Lapachone suppresses neuroinflammation by modulating the expression of cytokines and matrix metalloproteinases in activated microglia, J. Neuroinflamm. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
What the sources say
- Not checked yetcites [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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Toxic protein species and inflammatory stimuli may work in concert to enhance inflammatory signals via convergent and redundant pathways.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The TLDc domain is a highly conserved c-terminal domain motif shared by a small family of proteins that protect against oxidative stress in the CNS, such as oxidation resistance 1 (OXR1) and nuclear receptor coactivator 7 (NCOA7) [182].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.2. A Role for TLDc Proteins in Neuroinflammation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“For example, LPS and α-synuclein have a synergistic effect on the upregulation of several key mediators of the inflammatory response, including early activation of PKC, followed quickly by MAPKs and NFκB [84].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
What the sources say
- Not checked yetcites [84] Zhang, 2018, Minimally Toxic Dose of Lipopolysaccharide and α-Synuclein Oligomer Elicit Synergistic Dopaminergic Neurodegeneration: Role and Mechanism of Microglial NOX2 Activation, Mol. Neurobiol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“This expression profile concurs with other studies of DAM [10,37,78,124,194].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.2. At the Forefront of Drug Discovery: ToxSeq Analysis of ROS-Generating Microglia
What the sources say
- Not checked yetcites [10] Deczkowska, 2018, Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration, Cell source
- Not checked yetcites [37] Hickman, 2018, Microglia in neurodegeneration, Nat. Neurosci. source
- Not checked yetcites [78] Gyoneva, S., Hosur, R., Gosselin, D., Zhang, B., Ouyang, Z., Cotleur, A.C., Peterson, M., Allaire, N., Challa, R., and Cullen, P. (2019). Cx3cr1-deficient microglia exhibit a premature aging transcriptome. Life Sci. Alliance, 2. source
- Not checked yetcites [124] Hickman, 2013, The microglial sensome revealed by direct RNA sequencing, Nat. Neurosci. source
- Not checked yetcites [194] Wes, 2016, Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease, Glia source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Nrf2 is a basic leucine zipper transcription factor that upregulates genes via interaction with an antioxidant response element (ARE), e.g., genes encoding NADH-quinone oxidoreductase 1 (NQO1) and glutathione-S-transferases (GSTs) [167].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
What the sources say
- Not checked yetcites [167] Itoh, 1997, An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements, Biochem. Biophys. Res. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, ROS from both NOX and the mitochondria contribute to inflammatory activation of microglia.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, heme oxygenase-1 (HO-1), an antioxidant enzyme upregulated by Nrf2, inhibited NOX2 activation in smooth muscle cells and LPS-stimulated macrophages [171,172].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
What the sources say
- Not checked yetcites [171] Lanone, 2005, Mitochondrial respiratory chain and NAD(P)H oxidase are targets for the antiproliferative effect of carbon monoxide in human airway smooth muscle, J. Biol. Chem. source
- Not checked yetcites [172] Lanone, 2005, Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: Implications for protection against endotoxic shock in rats, FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These pro-inflammatory, pro-oxidant pathways are balanced by antioxidant proteins that limit inflammation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The mechanisms leading to ROS production and release by microglia have been explored, especially in CAA where NOX activation likely involves fibrin-related clotting factors and IL13 signalling [104,126].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
What the sources say
- Not checked yetcites [104] Merlini, 2019, Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model, Neuron source
- Not checked yetcites [126] Park, 2009, IL-13-induced oxidative stress via microglial NADPH oxidase contributes to death of hippocampal neurons in vivo, J. Immunol. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Discovery of antioxidant/anti-inflammatory drugs that effectively modulate oxidative stress has been hindered by the lack of effective pre-clinical models and understanding of molecular mechanisms that underpin neuroinflammation and ROS production [195].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.2. At the Forefront of Drug Discovery: ToxSeq Analysis of ROS-Generating Microglia
What the sources say
- Not checked yetcites [195] Patel, 2016, Targeting Oxidative Stress in Central Nervous System Disorders, Trends Pharmacol. Sci. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Probably not a substantial claim. 24
- It may state two separate claims as one. 61
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.2. Microglial Activation and Oxidative Stress Are Hallmarks of Neurodegenerative Disease
What the sources say
- Not checked yetcites [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 yetcites [28] Klegeris, 1997, beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate, J. Neurosci. Res. source
- Not checked yetcites [29] Schilling, 2011, Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia, J. Cell. Physiol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.2. Microglial Activation and Oxidative Stress Are Hallmarks of Neurodegenerative Disease
What the sources say
- Not checked yetcites [12] Mielke, 2011, Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease, Am. J. Pathol. source
- Not checked yetcites [13] Hickman, 2008, Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer’s Disease Mice, J. Neurosci. source
- Not checked yetcites [14] Zhao, 2017, Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease, Mol. Neurodegener. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.2. Microglial Activation and Oxidative Stress Are Hallmarks of Neurodegenerative Disease
What the sources say
- Not checked yetcites [24] Croisier, 2005, Microglial inflammation in the parkinsonian substantia nigra: Relationship to alpha-synuclein deposition, J. Neuroinflamm. source
- Not checked yetcites [25] Su, 2008, Synuclein activates microglia in a model of Parkinson’s disease, Neurobiol. Aging source
- Not checked yetcites [26] Kim, 2013, Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia, Nat. Commun. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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]”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.2. Microglial Activation and Oxidative Stress Are Hallmarks of Neurodegenerative Disease
What the sources say
- Not checked yetcites [30] Sung, 2004, Lipid peroxidation and oxidative imbalance: Early functional events in Alzheimer’s disease, J. Alzheimers Dis. JAD source
- Not checked yetcites [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 yetcites [32] Lovell, 1995, Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease, Neurology source
- Not checked yetcites [33] Subbarao, 1990, Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro, J. Neurochem. source
- Not checked yetcites [34] Hensley, 1995, Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation, J. Neurochem. source
- Not checked yetcites [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 yetcites [36] Mecocci, 1994, Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease, Ann. Neurol. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it is hypothesised that elevated and dysregulated ROS production from DAM contributes to oxidative stress, leading to neuronal death.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 1. Introduction > 1.3. The Brain Is Especially Susceptible to Oxidative Stress
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. The authors may not put it forward as true.
None of the sources cited for this claim have been checked yet.
In the paper
“Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > Abstract
What the sources say
- Not checked yetcites [42] Heneka, 2015, Neuroinflammation in Alzheimer’s disease, Lancet Neurol. source
- Not checked yetcites [43] Trushina, 2017, Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease, J. Alzheimers Dis. JAD source
- Not checked yetcites [44] Reiss, 2018, Amyloid toxicity in Alzheimer’s disease, Rev. Neurosci. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.1. NOX2 and NOX4 Are Activated by Acute, Pro-Inflammatory Stimulation of Microglia
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [113] Shimohama, 2000, Activation of NADPH oxidase in Alzheimer’s disease brains, Biochem. Biophys. Res. Commun. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“NOX4 is expressed in the mammalian brain, however specific proteomic expression in microglia is unknown.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
What the sources say
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 2. Inflammatory-Related ROS Production—NOX Mediates Production of ROS in Microglia > 2.1. NOX Are a Family of Enzyme Subunits that Mediate Deliberate Production of ROS in Inflammation
What the sources say
- Not checked yetcites [58] Darrah, 2000, Cooperation between reactive oxygen and nitrogen intermediates in killing of Rhodococcus equi by activated macrophages, Infect. Immun. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia
What the sources say
- Not checked yetcites [68] Ansari, 2011, NADPH-oxidase activation and cognition in Alzheimer disease progression, Free Radic. Biol. Med. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.2. Damage-Associated Molecular Patterns (DAMPs) Originating from Neurons Mediate NOX Activation via Pattern Recognition Receptors CR3 and TLR4
What the sources say
- Not checked yetcites [86] Hou, 2018, Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway, Redox Biol. source
- Not checked yetcites [96] Bell, 2013, Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury, Circulation source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 2. Inflammatory-Related ROS Production—NOX Mediates Production of ROS in Microglia > 2.1. NOX Are a Family of Enzyme Subunits that Mediate Deliberate Production of ROS in Inflammation
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 2. Inflammatory-Related ROS Production—NOX Mediates Production of ROS in Microglia > 2.1. NOX Are a Family of Enzyme Subunits that Mediate Deliberate Production of ROS in Inflammation
What the sources say
- Not checked yetcites [46] Berendes, 1957, A fatal granulomatosus of childhood: The clinical study of a new syndrome, Minn. Med.
- Not checked yetcites [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 yetcites [48] Baehner, 1967, Leukocyte oxidase: Defective activity in chronic granulomatous disease, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 3. Expression and Regulation of NOX in Microglia > Microglia Express NOX2 and NOX4
What the sources say
- Not checked yetcites [72] Zhang, 2014, An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex, J. Neurosci. source
- Not checked yetcites [73] Zhang, 2016, Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse, Neuron source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.2. Damage-Associated Molecular Patterns (DAMPs) Originating from Neurons Mediate NOX Activation via Pattern Recognition Receptors CR3 and TLR4
What the sources say
- Not checked yetcites [85] Fu, 2012, Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia, Glia source
- Not checked yetcites [98] Zhang, 2011, Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity, J. Neuroinflamm. source
- Not checked yetcites [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
- Not checked yetcites [100] Akiyama, 1990, Brain microglia constitutively express beta-2 integrins, J. Neuroimmunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.2. Damage-Associated Molecular Patterns (DAMPs) Originating from Neurons Mediate NOX Activation via Pattern Recognition Receptors CR3 and TLR4
What the sources say
- Not checked yetcites [64] Cooney, 2013, Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury, J. Neuroinflamm. source
- Not checked yetcites [102] Levesque, 2013, The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function, J. Neurochem. source
- Not checked yetcites [103] Pei, 2007, MAC1 mediates LPS-induced production of superoxide by microglia: The role of pattern recognition receptors in dopaminergic neurotoxicity, Glia source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The rate-limiting step of NOX2 activation is hypothesised to be serine-threonine phosphorylation of p47phox by p21 (cdc42/Rac1)-activated kinase-1 [62].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 2. Inflammatory-Related ROS Production—NOX Mediates Production of ROS in Microglia > 2.3. Phagocytic NOX (NOX1-3) Are Regulated by the Assembly of Cytosolic Subunits
What the sources say
- Not checked yetcites [62] Roepstorff, 2008, Stimulus-dependent Regulation of the Phagocyte NADPH Oxidase by a VAV1, Rac1, and PAK1 Signaling Axis, J. Biol. Chem. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nonetheless, NOX is activated in in vivo models of AD and offsetting this upregulation may limit neurodegeneration and cognitive impairment.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Evidence from mammalian studies indicates that NOX activation in response to amyloid-β contributes to neurodegeneration and is associated with cerebrovascular pathology.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Further, microglia in AD brains strongly express gp91phox, implying NOX2 activation is localised to microglia in AD [119].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [119] Gupta, 2010, NOX activity is increased in mild cognitive impairment, Antioxid. Redox Signal. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Indeed, Aβ-42 induces NOX2 expression in microglia and this response is accentuated in aged mice [125].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [140] Dresselhaus, E.C., and Meffert, M.K. (2019). Cellular Specificity of NF-κB Function in the Nervous System. Front. Immunol., 10. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [117] Gupta, 2011, Cognitive impairment in humanized APP×PS1 mice is linked to Aβ(1-42) and NOX activation, Neurobiol. Dis. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Also, NOX1 and 3 expression is increased in early AD, followed by upregulation of markers of mitochondrial dysfunction [114].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“NFκB activation by TLR4 signalling results in neuroinflammation and cognitive impairment [141,142].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Knockdown of gp91phox or application of N-acetyl cysteine (the antioxidant, NAC) in infected macrophages reduced NFκB activation levels.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 4. Microglial NOX Is Activated in Inflammation and Neurodegeneration > 4.3. NOX Is Activated in Chronic Disease-Associated Microglia (DAM)—A Focus on Alzheimer’s Disease
What the sources say
- Not checked yetcites [113] Shimohama, 2000, Activation of NADPH oxidase in Alzheimer’s disease brains, Biochem. Biophys. Res. Commun. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [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 yetcites [139] Zheng, 2011, Structural studies of NF-κB signaling, Cell Res. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Interestingly, GRN−/− mice display high numbers of LDAM which are ROS-generating and pro-inflammatory, yet defective in phagocytosis [162].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
- Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The family includes extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPKs.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
- Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source
- Not checked yetcites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source
- Not checked yetcites [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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Ethanol-related neurodegeneration is associated with increased microglial NFκB activation and gp91phox expression [150].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [150] Qin, 2012, NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration, J. Neuroinflamm. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease
What the sources say
- Not checked yetcites [160] Jackson, 2019, Lipid droplet biogenesis, Curr. Opin. Cell Biol. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.1. NFκB, a Master Regulator of Inflammation in Microglia, Is Associated with NOX Expression
What the sources say
- Not checked yetcites [150] Qin, 2012, NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration, J. Neuroinflamm. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Antioxidant treatment or human superoxide dismutase 1 (SOD1) expression in flies reduces LD formation and attenuates neurodegeneration [163].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.1. Lipid Droplet Accumulation Is Stimulated by ROS and Correlated with Neuronal Death
What the sources say
- Not checked yetcites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“MAPKs themselves exert their effects on cellular physiology via myriad effectors, including transcription factors and further kinases [152].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [152] Kaminska, 2009, MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target, Anat. Rec. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 5. ROS Are Secondary Messengers Activating Pro-inflammatory Pathways in Microglia > 5.2. ROS Serves to Activate the MAPK Family Resulting in Microglial Activation
What the sources say
- Not checked yetcites [152] Kaminska, 2009, MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target, Anat. Rec. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, NCOA7 is induced in epithelial cells in response to rhinovirus infection and LPS-stimulated macrophages, the peripheral myeloid cousins of microglia [186,187].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.2. A Role for TLDc Proteins in Neuroinflammation
What the sources say
- Not checked yetcites [186] Baines, 2013, Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD, Respir. Res. source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.2. A Role for TLDc Proteins in Neuroinflammation
What the sources say
- Not checked yetcites [184] Liu, 2015, Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis, Brain source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Expression of these proteins by Nrf2 in microglia may represent a pathway that can be modulated to enhance innate defences and combat oxidative stress.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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]).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Intracranial injection of the isothiocyanate, sulforaphane, enhanced Nrf2 levels which limited expression of pro-inflammatory microglial markers and conferred neuroprotection [168,169,170].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
What the sources say
- Not checked yetcites [168] Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol. Baltim. source
- Not checked yetcites [169] Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease, Glia source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, LDAM are important regulators of oxidative stress and a mechanism by which protective inflammation may become dysregulated and damaging in ageing and neurodegeneration.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“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).”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.2. At the Forefront of Drug Discovery: ToxSeq Analysis of ROS-Generating Microglia
What the sources say
- Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.2. Lipid-Droplet Accumulating Microglia May Represent a Double-Edged Sword in Neurodegeneration
What the sources say
- Not checked yetcites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“This implies LDAM are dysfunctional in neurodegeneration, where they may be unable to clear aggregated protein but would induce oxidative stress and inflammatory cascades.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.2. Lipid-Droplet Accumulating Microglia May Represent a Double-Edged Sword in Neurodegeneration
What the sources say
- Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Molecular pathways in microglia contributing to neurodegeneration undoubtedly involve inflammatory-mediated ROS production by activation of NOX.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.2. A Role for TLDc Proteins in Neuroinflammation
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.2. A Role for TLDc Proteins in Neuroinflammation
What the sources say
- Not checked yetcites [185] Doyle, 2018, The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry, Nat. Microbiol. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“However, LDAM are also ROS-generating and pro-inflammatory yet defective in phagocytosis in murine models [162].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 6. Lipid Droplet-Accumulating Microglia as a Source of OS in Neurodegenerative Disease > 6.2. Lipid-Droplet Accumulating Microglia May Represent a Double-Edged Sword in Neurodegeneration
What the sources say
- Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Microgliosis and sulforaphane neuroprotection were attenuated in Nrf2-deficient mice which confirms a mechanistic link between Nrf2 and immune regulation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
What the sources say
- Not checked yetcites [168] Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol. Baltim. source
- Not checked yetcites [169] Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease, Glia source
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.2. A Role for TLDc Proteins in Neuroinflammation
What the sources say
- Not checked yetcites [191] Shkolnik, 2008, Molecular characterization and bioinformatics analysis of Ncoa7B, a novel ovulation-associated and reproduction system-specific Ncoa7 isoform, Reproduction source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Notably, many experiments examining the role have been conducted in immortalised microglia, e.g., BV2 cells.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 7. Balancing the Scales—Antioxidant Enzymes Limit Microglial Activation > 7.1. Expression of Classical Antioxidant Proteins Are Controlled by Nrf2 in Microglia
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This likely involves a vicious cycle in which neuroinflammatory signals induce ROS release, which then promotes further deleterious inflammation.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.1. Understanding the Molecular Mechanisms of Neuroinflammation Is Key to Developing Effective Antioxidant Therapies
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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].”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.2. At the Forefront of Drug Discovery: ToxSeq Analysis of ROS-Generating Microglia
What the sources say
- Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.2. At the Forefront of Drug Discovery: ToxSeq Analysis of ROS-Generating Microglia
What the sources say
- Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Acivin effectively reduced oxidative stress and neuronal death in the EAE model without toxicity to other CNS cell types.”
§ ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease > 8. Conclusions and Future Directions > 8.2. At the Forefront of Drug Discovery: ToxSeq Analysis of ROS-Generating Microglia
What the sources say
- Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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?
In the citing paper
“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]
In the citing paper
“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]
Citations
Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226
Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., et al. (2010) · Science · doi:10.1126/science.1194637 · Cited by 5,175 · cited 1×
“Whilst peripheral macrophages and microglia share origin in the yolk sac, microglia are an ontogenetically distinct, locally maintained cell population [69,70] and so NOX expression in microglia may not exactly mirror that of their macrophage relatives.”
BackgroundZhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · cited 5×
“There remains a small increase in ROS production in response to LPS and α-synuclein in these NOX2 knockout cultures, likely a result of NOX4, since this isoform is expressed at the next highest level in microglia [72].”
BackgroundInfluentialMicroglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · cited 1×
“Considering CR3 signalling is an essential functional component in synaptic pruning by microglia [93], NOX activation by PRRs is likely a functional inflammatory-related phagocytic response to eliminate dead and dying neurons and aggregated protein, which has been elucidated by 2-photon live imaging [94,95].”
BackgroundItoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6943 · Cited by 3,999 · cited 1×
“, genes encoding NADH-quinone oxidoreductase 1 (NQO1) and glutathione-S-transferases (GSTs) [167].”
Toll-like receptors and their crosstalk with other innate receptors in infection and immunity
Kawai, T., & Akira, S. (2011) · Immunity · doi:10.1016/j.immuni.2011.05.006 · Cited by 3,658 · cited 6×
“These signals are transduced in microglia by nuclear factor κB (NFκB) and mitogen-activated protein kinases (MAPKs), such as p38 and extracellular signal-regulated kinase (ERK).”
BackgroundInfluentialOncogenic Signaling Pathways in The Cancer Genome Atlas
Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.035 · Cited by 3,201 · cited 1×
“Investigating this dynamic interaction between convergent pro-inflammatory pathways, similar to what has been divulged in oncogenic pathways in cancer [193], will be key to understanding inappropriate inflammation in neurodegenerative disease.”
BackgroundNOX enzymes and the biology of reactive oxygen
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Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · cited 1×
“Characterisation of gene ontology networks in post-mortem AD brains has identified dysregulation of microglia-specific networks as the most strongly correlated to neuropathology [15] and many microglial AD risk-factor genes have been identified [16,17].”
Background
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Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy
Forman, H. J., & Zhang, H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00233-1 · Cited by 2,900
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“ROS-mediated stress has been shown to impact the immune function of microglial cells in both inflammatory responses and neurodegenerative disorders 136 .”
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“Increased markers of inflammation and oxidative stress have been recently demonstrated in many distinct disorders including cancer [1,2], cardiovascular diseases [3,4], metabolic disorders including diabetes [5,6], chronic kidney disease [7,8], and neurodegenerative disorders [9,10].”
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“Thus, therapeutic methods by targeting ROS in microglia may be helpful to reduce neuroinflammatory damage [20, 21] .”
Background
Metadata
- Authors
- Simpson, D. S. A., & Oliver, P. L.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Oliver, Peter L.
- Venue
- Antioxidants
- Publisher
- MDPI AG
- Published
- 2020-08-13
- Volume
- 9
- Issue
- 8
- Pages
- 743
- ISSN
- 2076-3921 (ISSN-L)
- 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
- gold
- doi.org
- 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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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