β-Amyloid Stimulation of Microglia and Monocytes Results in TNFα-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis
Open accessAbstract
Reactive microglia associated with the β-amyloid plaques in Alzheimer's disease (AD) brains initiate a sequence of inflammatory events integral to the disease process. We have observed that fibrillar β-amyloid peptides activate a tyrosine kinase-based signaling response in primary mouse microglia and the human monocytic cell line, THP-1, resulting in production of neurotoxic secretory products, proinflammatory cytokines, and reactive oxygen species. We report that most of the amyloid-induced tyrosine kinase activity was stimulated after activation of Src family members such as Lyn. However, transduction of the signaling response required for increased production of the cytokines TNFα and IL1-β was mediated by the nonreceptor tyrosine kinase, Syk. Additionally, β-amyloid stimulated an NFκB-dependent pathway in parallel that was required for cytokine production. Importantly, TNFα generated by the monocytes and microglia was responsible for the majority of the neuorotoxic activity secreted by these cells after β-amyloid stimulation but must act in concert with other factors elaborated by microglia to elicit neuronal death. Moreover, we observed that the neuronal loss was apoptotic in nature and involved increased neuronal expression of inducible nitric oxide synthase and subsequent peroxynitrite production. Selective inhibitors of inducible nitric oxide synthase effectively protected cells from toxicity associated with the microglial and monocytic secretory products. This study demonstrates a functional linkage between β-amyloid-dependent activation of microglia and several characteristic markers of neuronal death occurring in Alzheimer's disease brains.
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?
Increased iNOS and decreased Arg-1 found in MG-AD are consistent with a pro-inflammatory status.
“The increased iNOS and decreased Arg-1 found in MG-AD are consistent with a pro-inflammatory status, as previously documented in AD microglia [105,106].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [106]
The introduction and Discussion (page unavailable) describe amyloid-stimulated microglia as pro-inflammatory. But the increased iNOS measured in this study was in neurons exposed to products from stimulated microglia, not in AD microglia, and the paper does not report decreased Arg-1. It therefore supports the inflammatory context, not the specific marker pattern attributed to AD microglia. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
MCGEER, P., & MCGEER, E. (1995) · Brain Research Reviews · doi:10.1016/0165-0173(95)00011-9 · Cited by 1,287 · see citing works
Risk of Alzheimer's disease and duration of NSAID use
Stewart, W. F., Kawas, C., Corrada, M., & Metter, E. J. (1997) · Neurology · doi:10.1212/wnl.48.3.626 · Cited by 1,132 · see citing works
Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease
Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S., & Selkoe, D. (1989) · Journal of Neuroimmunology · doi:10.1016/0165-5728(89)90115-x · Cited by 940 · see citing works
Nonsteroidal anti-inflammatory drugs in Alzheimer's disease
Rich, J. B., Rasmusson, D. X., Folstein, M. F., Carson, K. A., Kawas, C., & Brandt, J. (1995) · Neurology · doi:10.1212/wnl.45.1.51 · Cited by 446 · see citing works
Tarkowski, E., Blennow, K., Wallin, A., & Tarkowski, A. (1999) · Journal of Clinical Immunology · doi:10.1023/a:1020568013953 · Cited by 349 · see citing works
Yates, S. L., Burgess, L. H., Kocsis‐Angle, J., Antal, J. M., Dority, M. D., Embury, P. B., Piotrkowski, A. M., & Brunden, K. R. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0741017.x · Cited by 202 · see citing works
Galimberti, D., Baron, P., Meda, L., Prat, E., Scarpini, E., Delgado, R., Catania, A., Lipton, J. M., & Scarlato, G. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1276 · Cited by 83 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- McGeer PL, Schulzer M, McGeer EG (1996) Arthritis and anti- inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47:425-432.
Cited by
Sorted by citations
Querfurth, H. W., & LaFerla, F. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0909142 · Cited by 4,569 · see citing works
The NALP3 inflammasome is involved in the innate immune response to amyloid-β
Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J., & Golenbock, D. T. (2008) · Nature Immunology · doi:10.1038/ni.1636 · Cited by 2,441 · see citing works
Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253 · see citing works
Systemic infections and inflammation affect chronic neurodegeneration
Perry, V. H., Cunningham, C., & Holmes, C. (2007) · Nature Reviews Immunology · doi:10.1038/nri2015 · Cited by 1,027 · see citing works
Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease
Meyer-Luehmann, M., Spires-Jones, T. L., Prada, C., Garcia-Alloza, M., de Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D. M., Bacskai, B. J., & Hyman, B. T. (2008) · Nature · doi:10.1038/nature06616 · Cited by 987 · see citing works
Glycogen synthase kinase-3 (GSK3): Inflammation, diseases, and therapeutics
Jope, R. S., Yuskaitis, C. J., & Beurel, E. (2007) · Neurochemical Research · doi:10.1007/s11064-006-9128-5 · Cited by 774 · see citing works
Microglia Promote the Death of Developing Purkinje Cells
Marı́n-Teva, J. L., Dusart, I., Colin, C., Gervais, A., van Rooijen, N., & Mallat, M. (2004) · Neuron · doi:10.1016/s0896-6273(04)00069-8 · Cited by 757 · see citing works
SIRT1 Protects against Microglia-dependent Amyloid-β Toxicity through Inhibiting NF-κB Signaling
Chen, J., Zhou, Y., Mueller-Steiner, S., Chen, L.-F., Kwon, H., Yi, S., Mucke, L., & Gan, L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509329200 · Cited by 740 · see citing works
Chong, Z. Z., Li, F., & Maiese, K. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.02.004 · Cited by 536 · see citing works
CD36 Mediates the Innate Host Response to β-Amyloid
El Khoury, J. B., Moore, K. J., Means, T. K., Leung, J., Terada, K., Toft, M., Freeman, M. W., & Luster, A. D. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021546 · Cited by 483 · see citing works
Inflammatory markers and the risk of Alzheimer disease: The Framingham Study
Tan, Z. S., Beiser, A. S., Vasan, R. S., Roubenoff, R., Dinarello, C. A., Harris, T. B., Benjamin, E. J., Au, R., Kiel, D. P., Wolf, P. A., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000263217.36439.da · Cited by 440 · see citing works
Neuroinflammatory processes in Alzheimer’s disease
Heneka, M. T., O’Banion, M. K., Terwel, D., & Kummer, M. P. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0438-z · Cited by 433 · see citing works
Inflammatory process in Alzheimer's Disease
Meraz-Ríos, M. A., Toral-Rios, D., Franco-Bocanegra, D., Villeda-Hernández, J., & Campos-Peña, V. (2013) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2013.00059 · Cited by 427 · see citing works
Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms
Sastre, M., Klockgether, T., & Heneka, M. T. (2006) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2005.11.014 · Cited by 426 · see citing works
Suzuki, T., Hide, I., Ido, K., Kohsaka, S., Inoue, K., & Nakata, Y. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3792-03.2004 · Cited by 394 · see citing works
Liao, Y.-F., Wang, B.-J., Cheng, H.-T., Kuo, L.-H., & Wolfe, M. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402034200 · Cited by 389 · see citing works
Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
Neher, J. J., Neniskyte, U., Zhao, J.-W., Bal-Price, A., Tolkovsky, A. M., & Brown, G. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003600 · Cited by 373 · see citing works
The Neuropathology of Septic Shock
Sharshar, T., Annane, D., de la Gradmaison, G. L., Brouland, J. P., Hopkinson, N. S., & Gray, F. (2004) · Brain Pathology · doi:10.1111/j.1750-3639.2004.tb00494.x · Cited by 348 · see citing works
Sharshar, T., Gray, F., de la Grandmaison, G. L., Hopklnson, N. S., Ross, E., Dorandeu, A., Orlikowski, D., Raphael, J.-C., Gajdos, P., & Annane, D. (2003) · The Lancet · doi:10.1016/s0140-6736(03)14899-4 · Cited by 341 · see citing works
Immunology and immunotherapy of Alzheimer's disease
Weiner, H. L., & Frenkel, D. (2006) · Nature Reviews Immunology · doi:10.1038/nri1843 · Cited by 335 · see citing works
A CD36-initiated Signaling Cascade Mediates Inflammatory Effects of β-Amyloid
Moore, K. J., El Khoury, J., Medeiros, L. A., Terada, K., Geula, C., Luster, A. D., & Freeman, M. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208788200 · Cited by 327 · see citing works
Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia
Sondag, C. M., Dhawan, G., & Combs, C. K. (2009) · Journal of Neuroinflammation · doi:10.1186/1742-2094-6-1 · Cited by 295 · see citing works
Self-citationThe dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ
Zheng, C., Zhou, X.-W., & Wang, J.-Z. (2016) · Translational Neurodegeneration · doi:10.1186/s40035-016-0054-4 · Cited by 292 · see citing works
Oxidative stress and β-amyloid protein in Alzheimer’s disease
Cai, Z., Zhao, B., & Ratka, A. (2011) · NeuroMolecular Medicine · doi:10.1007/s12017-011-8155-9 · Cited by 279 · see citing works
Aging‐dependent changes of microglial cells and their relevance for neurodegenerative disorders
Von Bernhardi, R., Tichauer, J. E., & Eugenín, J. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06537.x · Cited by 258 · see citing works
McKim, S. E., Gäbele, E., Isayama, F., Lambert, J. C., Tucker, L. M., Wheeler, M. D., Connor, H. D., Mason, R. P., Doll, M. A., Hein, D. W., et al. (2003) · Gastroenterology · doi:10.1053/j.gastro.2003.08.030 · Cited by 243 · see citing works
Mechanisms of Statin-mediated Inhibition of Small G-protein Function
Cordle, A., Koenigsknecht-Talboo, J., Wilkinson, B., Limpert, A., & Landreth, G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505268200 · Cited by 235 · see citing works
Self-citationJanelsins, M. C., Mastrangelo, M. A., Park, K. M., Sudol, K. L., Narrow, W. C., Oddo, S., LaFerla, F. M., Callahan, L. M., Federoff, H. J., & Bowers, W. J. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.080528 · Cited by 220 · see citing works
Critical role for NLRP3 in necrotic death triggered by <i>Mycobacterium tuberculosis</i>
Wong, K., & Jacobs Jr, W. R. (2011) · Cellular Microbiology · doi:10.1111/j.1462-5822.2011.01625.x · Cited by 209 · see citing works
Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease
Farfara, D., Lifshitz, V., & Frenkel, D. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00314.x · Cited by 216 · see citing works
Sousa, M. M., Du Yan, S., Fernandes, R., Guimarães, A., Stern, D., & Saraiva, M. J. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-19-07576.2001 · Cited by 212 · see citing works
Biscaro, B., Lindvall, O., Tesco, G., Ekdahl, C. T., & Nitsch, R. M. (2012) · Neurodegenerative Diseases · doi:10.1159/000330363 · Cited by 164 · see citing works
Grommes, C., Lee, C. Y. D., Wilkinson, B. L., Jiang, Q., Koenigsknecht-Talboo, J. L., Varnum, B., & Landreth, G. E. (2008) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-007-9090-2 · Cited by 162 · see citing works
Self-citationAccumulation of tau induced in neurites by microglial proinflammatory mediators
Gorlovoy, P., Larionov, S., Pham, T. T. H., & Neumann, H. (2009) · The FASEB Journal · doi:10.1096/fj.08-123877 · Cited by 156 · see citing works
Koenigsknecht-Talboo, J., Meyer-Luehmann, M., Parsadanian, M., Garcia-Alloza, M., Finn, M. B., Hyman, B. T., Bacskai, B. J., & Holtzman, D. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4147-08.2008 · Cited by 149 · see citing works
Mutant α-Synuclein Overexpression Mediates Early Proinflammatory Activity
Su, X., Federoff, H. J., & Maguire-Zeiss, K. A. (2009) · Neurotoxicity Research · doi:10.1007/s12640-009-9053-x · Cited by 145 · see citing works
Doi, Y., Mizuno, T., Maki, Y., Jin, S., Mizoguchi, H., Ikeyama, M., Doi, M., Michikawa, M., Takeuchi, H., & Suzumura, A. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.090418 · Cited by 135 · see citing works
Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review
Edler, M. K., Mhatre-Winters, I., & Richardson, J. R. (2021) · Cells · doi:10.3390/cells10051138 · Cited by 126 · see citing works
Ryu, J. K., Cho, T., Choi, H. B., Wang, Y. T., & McLarnon, J. G. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2888-08.2009 · Cited by 121 · see citing works
Perluigi, M., Joshi, G., Sultana, R., Calabrese, V., De Marco, C., Coccia, R., Cini, C., & Butterfield, D. A. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.20879 · Cited by 125 · see citing works
Tobinick, E. (2009) · CNS Drugs · doi:10.2165/11310810-000000000-00000 · Cited by 117 · see citing works
DNA damage in the oligodendrocyte lineage and its role in brain aging
Tse, K.-H., & Herrup, K. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.05.006 · Cited by 108 · see citing works
Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β
Kauppinen, T. M., Suh, S., Higashi, Y., Berman, A. E., Escartin, C., Won, S., Wang, C., Cho, S.-H., Gan, L., & Swanson, R. A. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-152 · Cited by 112 · see citing works
Distinct Signaling Pathways Regulate TREM2 Phagocytic and NFκB Antagonistic Activities
Yao, H., Coppola, K., Schweig, J. E., Crawford, F., Mullan, M., & Paris, D. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00457 · Cited by 110 · see citing works
Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway
Kovac, A., Zilka, N., Kazmerova, Z., Cente, M., Zilkova, M., & Novak, M. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100216 · Cited by 75 · see citing works
Loane, D. J., Washington, P. M., Vardanian, L., Pocivavsek, A., Hoe, H.-S., Duff, K. E., Cernak, I., Rebeck, G. W., Faden, A. I., & Burns, M. P. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2010.1595 · Cited by 57 · see citing works
Campos-Peña, V., Toral-Rios, D., Becerril-Pérez, F., Sánchez-Torres, C., Delgado-Namorado, Y., Torres-Ossorio, E., Franco-Bocanegra, D., & Carvajal, K. (2017) · Antioxidants & Redox Signaling · doi:10.1089/ars.2016.6768 · Cited by 58 · see citing works
Garcia, G., Pinto, S., Ferreira, S., Lopes, D., Serrador, M. J., Fernandes, A., Vaz, A. R., Mendonça, A. D., Edenhofer, F., Malm, T., et al. (2022) · Cells · doi:10.3390/cells11213377 · Cited by 55 · see citing works
“While iNOS is known to be stimulated in AD microglia, generating nitric oxide (NO) and causing neuronal apoptosis [106], its substrate competitor Arg-1 promotes the microglial clearance of Aβ during neuroinflammation [107].”
BackgroundResultInflammation: good or bad for ADHD?
Donev, R., & Thome, J. (2010) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-010-0038-7 · Cited by 54 · see citing works
Apolipoprotein J (clusterin) activates rodent microglia <i>in vivo</i> and <i>in vitro</i>
Xie, Z., Harris‐White, M. E., Wals, P. A., Frautschy, S. A., Finch, C. E., & Morgan, T. E. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03065.x · Cited by 53 · see citing works
Anti-Neuroinflammatory Potential of Polyphenols by Inhibiting NF-Κb to Halt Alzheimer's Disease
Uddin, M. S., Hasana, S., Ahmad, J., Hossain, M. F., Rahman, M. M., Behl, T., Rauf, A., Ahmad, A., Hafeez, A., Perveen, A., et al. (2021) · Current Pharmaceutical Design · doi:10.2174/1381612826666201118092422 · Cited by 49 · see citing works
Guo, Q., Li, Y., Xu, S., Wang, P., Qian, K., Yang, P., Sheng, D., Wang, L., Cheng, Y., Meng, R., et al. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.01.074 · Cited by 40 · see citing works
New therapeutic avenues of MCSF for brain diseases and injuries
Pons, V., & Rivest, S. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00499 · Cited by 35 · see citing works
- Authors
- Combs, C. K., Karlo, J. C., Kao, S.-C., & Landreth, G. E.
- Affiliations
- Case Western Reserve University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-02-15
- Volume
- 21
- Issue
- 4
- Pages
- 1179-1188
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762255
- OpenAlex
- W2135482947
- Cited by
- 721
- References
- 8
- Citations by year
- 2026: 12 · 2025: 23 · 2024: 49 · 2023: 30 · 2022: 22 · 2021: 24 · 2020: 26 · 2019: 24 · 2018: 15 · 2017: 22 · 2016: 26 · 2015: 30 · 2014: 27 · 2013: 30 · 2012: 35
- FWCI
- 17.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG08012)
- National Institute on Aging (AG-08012, P50AG008012, R01AG016740, AG-16740)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD0710422)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- amyloid-beta, Alzheimer's disease, microglia, monocytes, TNF-α, inducible nitric oxide synthase, neuronal apoptosis, Lyn kinase, Src family kinases, NF-κB signaling, IL-1β, peroxynitrite, neuroinflammation, neurotoxicity, THP-1 cells
- MeSH terms
- Syk Kinase, Contraindications, Alzheimer Disease, Animals, Cells, Cultured, Enzyme Precursors, Humans, Inflammation, Mice, Inbred C57BL, Monocytes, Neurons, Peptide Fragments, Protein-Tyrosine Kinases, Transcription Factors, Tumor Necrosis Factor-alpha, Signal Transduction, Amyloid beta-Peptides, NF-kappa B, Apoptosis, Microglia, Nitric Oxide Synthase, src-Family Kinases, Intracellular Signaling Peptides and Proteins, Mice, Nitric Oxide Synthase Type II
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
