Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging
Open accessAbstract
Abstract Microglia express constitutively a Nox2 enzyme that is involved in neuroinflammation by the generation of reactive oxygen species (ROS). Amyloid β (Aβ) plays a crucial role in Alzheimer’s disease. However, the mechanism of Aβ-induced microglial dysfunction and redox-regulation of microgliosis in aging remains unclear. In this study, we examined Nox2-derived ROS in mediating microglial response to Aβ peptide 1–42 (Aβ42) stimulation in vitro, in aging-associated microgliosis in vivo and in post-mortem human samples. Compared to controls, Aβ42 markedly induced BV2 cell ROS production, Nox2 expression, p47phox and ERK1/2 phosphorylation, cell proliferation and IL-1β secretion. All these changes could be inhibited to the control levels in the presence of Nox2 inhibitor or superoxide scavenger. Compared to young (3–4 months) controls, midbrain tissues from wild-type aging mice (20–22 months) had significantly higher levels of Nox2-derived ROS production, Aβ deposition, microgliosis and IL-1β production. However, these aging-related changes were reduced or absent in Nox2 knockout aging mice. Clinical significance of aging-associated Nox2 activation, microgliosis and IL-1β production was investigated using post-mortem midbrain tissues of humans at young (25–38 years) and old age (61–85 years). In conclusion, Nox2-dependent redox-signalling is crucial in microglial response to Aβ42 stimulation and in aging-associated microgliosis and brain inflammation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
NOX activation is evident in the Alzheimer's disease brain, and NOX2 is highly expressed in microglia.
“NOX activation is evident in the AD brain, in addition NOX2 is highly expressed in microglia [108,109].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [109]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Bedard, K., & Krause, K.-H. (2007) · Physiological Reviews · doi:10.1152/physrev.00044.2005 · Cited by 6,989 · see citing works
Oxidative stress and the amyloid beta peptide in Alzheimer’s disease
Cheignon, C., Tomas, M., Bonnefont-Rousselot, D., Faller, P., Hureau, C., & Collin, F. (2018) · Redox Biology · doi:10.1016/j.redox.2017.10.014 · Cited by 2,185 · see citing works
Microglia emerge as central players in brain disease
Salter, M. W., & Stevens, B. (2017) · Nature Medicine · doi:10.1038/nm.4397 · Cited by 1,767 · see citing works
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Condello, C., Yuan, P., Schain, A., & Grutzendler, J. (2015) · Nature Communications · doi:10.1038/ncomms7176 · Cited by 718 · see citing works
Microglia during development and aging
Harry, G. J. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.04.013 · Cited by 524 · see citing works
Butterfield, D. A., & Boyd-Kimball, D. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170543 · Cited by 403 · see citing works
Park, L., Zhou, P., Pitstick, R., Capone, C., Anrather, J., Norris, E. H., Younkin, L., Younkin, S., Carlson, G., McEwen, B. S., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711568105 · Cited by 332 · see citing works
Indices of lipid peroxidation in vivo: strengths and limitations
Meagher, E. A., & FitzGerald, G. A. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00232-x · Cited by 299 · see citing works
The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer's disease.
Wilkinson, B. L., & Landreth, G. E. (2006) · Journal of Neuroinflammation · doi:10.1186/1742-2094-3-30 · Cited by 235 · see citing works
Microglia and CNS Interleukin-1: Beyond Immunological Concepts
Liu, X., & Quan, N. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00008 · Cited by 224 · see citing works
Kumar, A., Barrett, J. P., Alvarez-Croda, D.-M., Stoica, B. A., Faden, A. I., & Loane, D. J. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.07.158 · Cited by 213 · see citing works
Old Maids: Aging and Its Impact on Microglia Function
Koellhoffer, E. C., McCullough, L. D., & Ritzel, R. M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040769 · Cited by 205 · see citing works
Microglia Proliferation Is Regulated by Hydrogen Peroxide from NADPH Oxidase
Mander, P. K., Jekabsone, A., & Brown, G. C. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.2.1046 · Cited by 198 · see citing works
β-Amyloid Is Different in Normal Aging and in Alzheimer Disease
Piccini, A., Russo, C., Gliozzi, A., Relini, A., Vitali, A., Borghi, R., Giliberto, L., Armirotti, A., D’Arrigo, C., Bachi, A., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501694200 · Cited by 192 · see citing works
Haslund‐Vinding, J., McBean, G., Jaquet, V, & Vilhardt, F. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13425 · Cited by 169 · see citing works
Clearance of Amyloid-β Peptides By Microglia and Macrophages: the Issue of What, When and Where
Lai, A. Y., & McLaurin, J. (2012) · Future Neurology · doi:10.2217/fnl.12.6 · Cited by 161 · see citing works
Jekabsone, A., Mander, P. K., Tickler, A. K., Sharpe, M. A., & Brown, G. C. (2006) · Journal of Neuroinflammation · doi:10.1186/1742-2094-3-24 · Cited by 127 · see citing works
Green, S. P., Cairns, B., Rae, J., Errett-Baroncini, C., Hongo, J.-A. S., Erickson, R. W., & Curnutte, J. T. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200104000-00006 · Cited by 106 · see citing works
Redox proteomics and amyloid β-peptide: Insights into Alzheimer disease
Butterfield, D. A., & Boyd‐Kimball, D. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14589 · Cited by 105 · see citing works
Bussi, C., Peralta Ramos, J. M., Arroyo, D. S., Gaviglio, E. A., Gallea, J. I., Wang, J. M., Celej, M. S., & Iribarren, P. (2017) · Scientific Reports · doi:10.1038/srep43153 · Cited by 103 · see citing works
Filippo, M. D., de Iure, A., Giampà, C., Chiasserini, D., Tozzi, A., Orvietani, P. L., Ghiglieri, V., Tantucci, M., Durante, V., Quiroga‐Varela, A., et al. (2016) · Scientific Reports · doi:10.1038/srep20926 · Cited by 90 · see citing works
Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature
Fan, L. M., Geng, L., Cahill‐Smith, S., Liu, F., Douglas, G., McKenzie, C.-A., Smith, C., Brooks, G., Channon, K. M., & Li, J. (2019) · Journal of Clinical Investigation · doi:10.1172/jci125173 · Cited by 88 · see citing works
Self-citationCell damage produced by magnetic fluid hyperthermia on microglial BV2 cells
Calatayud, M. P., Soler, E., Torres, T. E., González, E. C., Junquera, C., Ibarra, M. R., & Goya, G. F. (2017) · Scientific Reports · doi:10.1038/s41598-017-09059-7 · Cited by 66 · see citing works
Fan, L. M., Cahill‐Smith, S., Geng, L., Du, J., Brooks, G., & Li, J. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.05.008 · Cited by 63 · see citing works
Self-citationOxidative Stress as a Biomarker for Alzheimer’S Disease
Collin, F., Cheignon, C., & Hureau, C. (2018) · Biomarkers in Medicine · doi:10.2217/bmm-2017-0456 · Cited by 58 · see citing works
Russo, R., Cattaneo, F., Lippiello, P., Cristiano, C., Zurlo, F., Castaldo, M., Irace, C., Borsello, T., Santamaria, R., Ammendola, R., et al. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.02.025 · Cited by 47 · see citing works
Ahlemeyer, B., Halupczok, S., Rodenberg-Frank, E., Valerius, K.-P., & Baumgart‐Vogt, E. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170923 · Cited by 46 · see citing works
Walton, J. C., Selvakumar, B., Weil, Z. M., Snyder, S. H., & Nelson, R. J. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.08.003 · Cited by 45 · see citing works
Mechanical stress increases brain amyloid β, tau, and α‐synuclein concentrations in wild‐type mice
Levy-Nogueira, M., Hamraz, M., Abolhassani, M., Bigan, E., Lafitte, O., Steyaert, J.-M., Dubois, B., & Schwartz, L. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.11.003 · Cited by 26 · see citing works
Detection of Nitric Oxide Formation in Primary Neural Cells and Tissues
Tjalkens, R. B., Carbone, D. L., & Wu, G. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-170-3_18 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Simpson, D. S. A., & Oliver, P. L. (2020) · Antioxidants · doi:10.3390/antiox9080743 · Cited by 1,044 · see citing works
Buccellato, F. R., D’Anca, M., Fenoglio, C., Scarpini, E., & Galimberti, D. (2021) · Antioxidants · doi:10.3390/antiox10091353 · Cited by 179 · see citing works
Malkov, A., Popova, I., Ivanov, A., Jang, S.-S., Yoon, S. Y., Osypov, A., Huang, Y., Zilberter, Y., & Zilberter, M. (2021) · Communications Biology · doi:10.1038/s42003-021-02551-x · Cited by 59 · see citing works
- Authors
- Geng, L., Fan, L. M., Liu, F., Smith, C., & Li, J. M.
- Affiliations
- University of Surrey (GB)
- University of Oxford (GB)
- University of Reading (GB)
- University of Edinburgh (GB)
- Corresponding author
- Li, Jian -Mei
- Venue
- Scientific Reports
- Published
- 2020-01-31
- Volume
- 10
- Issue
- 1
- Pages
- 1582-1582
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6994719
- OpenAlex
- W3003640680
- Cited by
- 69
- References
- 31
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 13 · 2023: 9 · 2022: 10 · 2021: 11 · 2020: 5
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-03-31)
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (acceptedVersion, cc-by)
- CentAUR (University of Reading) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Medical Research Council (MR/L016400/1)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- NOX2, NADPH oxidase, reactive oxygen species, microglia, amyloid-beta 42, microglial activation, aging, Alzheimer's disease, neuroinflammation, IL-1β, ERK1/2 phosphorylation, p47phox, redox signaling, BV-2 cells, midbrain
- MeSH terms
- NADPH Oxidase 2, Adult, Aged, Aged, 80 and over, Aging, Animals, Female, Humans, Male, Mice, Inbred C57BL, Microscopy, Fluorescence, Middle Aged, Oxidation-Reduction, Peptide Fragments, Amyloid beta-Peptides, Reactive Oxygen Species, Microglia, Mice, Knockout, Mice
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
