Connecting TNF-α Signaling Pathways to iNOS Expression in a Mouse Model of Alzheimer's Disease: Relevance for the Behavioral and Synaptic Deficits Induced by Amyloid β Protein
Open accessAbstract
Increased brain deposition of amyloid β protein (Aβ) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-α (TNF-α)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of both in vivo and in vitro approaches. The intracerebroventricular injection of Aβ 1–40 in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-α or iNOS reduced the cognitive deficit evoked by Aβ 1–40 in mice. Similar results were obtained in TNF-α receptor 1 and iNOS knock-out mice. Aβ 1–40 administration induced an increase in TNF-α expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Aβ 1–40 led to activation of both JNK (c-Jun-NH 2-terminal kinase)/c-Jun and nuclear factor-κB, resulting in iNOS upregulation in both brain structures. The anti-TNF-α antibody reduced all of the molecular and biochemical alterations promoted by Aβ 1–40. These results provide new insights in mouse models of AD, revealing TNF-α and iNOS as central mediators of Aβ action. These pathways might be targeted for AD drug development.
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?
Both iNOS and IL-1β signaling have been implicated in the loss of synaptic proteins in mouse models of Alzheimer's disease.
“whereas both iNOS and IL-1 signaling have been implicated in the loss of synaptic proteins in mouse models of Alzheimer's disease (Craft et al., 2005;Medeiros et al., 2007).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Medeiros et al., 2007
The Results section, “Prevention of synaptic dysfunction by TNF-α and iNOS inhibition” (page not provided), reports that iNOS inhibition or deletion protected against amyloid-β-induced loss of the synaptic protein synaptophysin in mice. The Discussion says further studies are needed to determine whether IL-1β participates; this paper does not establish the IL-1β part of the claim. (LLM, conf=0.88)
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
Missing Pieces in the NF-κB Puzzle
Ghosh, S., & Karin, M. (2002) · Cell · doi:10.1016/s0092-8674(02)00703-1 · Cited by 3,638 · see citing works
Activation of microglial cells by β-amyloid protein and interferon-γ
Meda, L., Cassatella, M. A., Szendrei, G. I., Otvos, L., Baron, P., Villalba, M., Ferrari, D., & Rossi, F. (1995) · Nature · doi:10.1038/374647a0 · Cited by 1,314 · see citing works
Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils
Khoury, J. E., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., & Loike, J. D. (1996) · Nature · doi:10.1038/382716a0 · Cited by 727 · see citing works
What's in a picture? The temptation of image manipulation
Rossner, M., & Yamada, K. M. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200406019 · Cited by 412 · see citing works
Nathan, C., Calingasan, N., Nezezon, J., Ding, A., Lucia, M. S., La Perle, K., Fuortes, M., Lin, M., Ehrt, S., Kwon, N. S., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20051529 · Cited by 214 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Masliah E, Achim CL, Ge N, DeTeresa R, Terry RD, Wiley CA (1992) Spec- trum of human immunodeficiency virus-associated neocortical damage. Ann Neurol 32:321-329.
Cited by
Sorted by citations
Jimenez, S., Baglietto-Vargas, D., Caballero, C., Moreno-Gonzalez, I., Torres, M., Sanchez-Varo, R., Ruano, D., Vizuete, M., Gutierrez, A., & Vitorica, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3024-08.2008 · Cited by 383 · see citing works
“The neuronal toxicity to TNF- , TNF- related factors and iNOS has been extensively probed (Cantarella et al., 2003; Lee et al., 2004; Li et al., 2004; Medeiros et al., 2007; Uberti et al., 2007).”
BackgroundPan, X.-D., Zhu, Y.-G., Lin, N., Zhang, J., Ye, Q.-Y., Huang, H.-P., & Chen, X.-C. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-45 · 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
Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase
Chéret, C., Gervais, A., Lelli, A., Colin, C., Amar, L., Ravassard, P., Mallet, J., Cumano, A., Krause, K.-H., & Mallat, M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3568-08.2008 · Cited by 225 · see citing works
Shi, J.-Q., Shen, W., Chen, J., Wang, B.-R., Zhong, L.-L., Zhu, Y.-W., Zhu, H.-Q., Zhang, Q.-Q., Zhang, Y.-D., & Xu, J. (2011) · Brain Research · doi:10.1016/j.brainres.2010.10.053 · Cited by 219 · see citing works
Tumor necrosis factor α Inhibition for Alzheimer’s Disease
Chang, R., Yee, K.-L., & Sumbria, R. K. (2017) · Journal of Central Nervous System Disease · doi:10.1177/1179573517709278 · Cited by 195 · see citing works
Current Concepts of Neurodegenerative Mechanisms in Alzheimer’s Disease
Magalingam, K. B., Radhakrishnan, A., Ping, N. S., & Haleagrahara, N. (2018) · BioMed Research International · doi:10.1155/2018/3740461 · Cited by 178 · see citing works
Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases
Nakamura, T., Prikhodko, O. A., Pirie, E., Nagar, S., Akhtar, M. W., Oh, C.-K., McKercher, S. R., Ambasudhan, R., Okamoto, S.-I., & Lipton, S. A. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.03.017 · Cited by 165 · see citing works
Frozza, R. L., Bernardi, A., Hoppe, J. B., Meneghetti, A. B., Matté, A., Battastini, A. M. O., Pohlmann, A. R., Guterres, S. S., & Salbego, C. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8401-2 · Cited by 165 · see citing works
Assini, F. L., Duzzioni, M., & Takahashi, R. N. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.06.005 · Cited by 161 · see citing works
Self-citationRole of TGFβ signaling in the pathogenesis of Alzheimer’s disease
von Bernhardi, R., Cornejo, F., Parada, G. E., & Eugenín, J. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00426 · Cited by 149 · see citing works
Accumulation 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
Targeting innate immunity for neurodegenerative disorders of the central nervous system
Andreasson, K. I., Bachstetter, A. D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D. C., Low, D., Lynch, M. A., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13667 · Cited by 126 · see citing works
Tobinick, E. (2009) · CNS Drugs · doi:10.2165/11310810-000000000-00000 · Cited by 117 · see citing works
Montgomery, S. L., Mastrangelo, M. A., Habib, D., Narrow, W. C., Knowlden, S. A., Wright, T. W., & Bowers, W. J. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.07.001 · Cited by 96 · see citing works
Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases
Knuesel, I. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.04.002 · Cited by 89 · see citing works
Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A
Liu, J., Wang, D., Li, S.-Q., Yu, Y., & Ye, R. D. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0493-y · Cited by 58 · see citing works
Li, Z., Yin, B., Zhang, S., Lan, Z., & Zhang, L. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115817 · Cited by 54 · see citing works
Ren, S., Breuillaud, L., Yao, W., Yin, T., Norris, K. A., Zehntner, S. P., & D’Adamio, L. (2021) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.016395 · Cited by 47 · see citing works
Involvement of hippocampal CAMKII/CREB signaling in the spatial memory retention induced by creatine
Souza, M. A., Magni, D. V., Guerra, G. P., Oliveira, M. S., Furian, A. F., Pereira, L., Marquez, S. V., Ferreira, J., Fighera, M. R., & Royes, L. F. F. (2012) · Amino Acids · doi:10.1007/s00726-012-1329-4 · Cited by 42 · see citing works
- Authors
- Medeiros, R., Prediger, R. D. S., Passos, G. F., Pandolfo, P., Duarte, F. S., Franco, J. L., Dafre, A. L., Di Giunta, G., Figueiredo, C. P., Takahashi, R. N., Campos, M. M., & Calixto, J. B.
- Affiliations
- Universidade Federal de Santa Catarina (BR)
- Pontifícia Universidade Católica do Rio Grande do Sul (BR)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-05-16
- Volume
- 27
- Issue
- 20
- Pages
- 5394-5404
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672347
- OpenAlex
- W2040536037
- Cited by
- 292
- References
- 5
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 7 · 2023: 11 · 2022: 8 · 2021: 11 · 2020: 14 · 2019: 11 · 2018: 9 · 2017: 13 · 2016: 17 · 2015: 20 · 2014: 21 · 2013: 15 · 2012: 18
- FWCI
- 16.44
- 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)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, TNF signaling, inducible nitric oxide synthase, cognitive impairment, learning and memory, synaptic dysfunction, glial activation, JNK/c-Jun pathway, NF-κB, oxidative stress, prefrontal cortex, hippocampus, anti-TNF therapy, mouse model
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Injections, Intraventricular, Male, Memory Disorders, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Signal Transduction, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, Mice, Knockout, 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
