The role of TNF-α signaling pathway on COX-2 upregulation and cognitive decline induced by β-amyloid peptide
Abstract
Alzheimer's disease (AD), a chronic degenerative and inflammatory brain disorder characterized by neuronal dysfunction and loss, is linked to accumulation of beta-amyloid (Abeta) peptide. Tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) are proteins that have key roles in immune cell activation, inflammation and cognitive function in the brain. Here, we evaluated the link between TNF-alpha and COX-2 on the acute responses elicited by Abeta. Behavioral and molecular analyses were performed in mice after an intracerebroventricular (i.c.v.) injection of Abeta(1-40). Genetic and/or pharmacological approaches were used to inhibit TNF-alpha and COX-2. I.c.v. Abeta(1-40) injection in mice activates TNF-alpha signaling pathway resulting in COX-2 upregulation, synaptic loss and cognitive decline. Pharmacological studies revealed that COX-2 is involved in the cognitive impairment mediated by TNF-alpha. However, COX-2 inhibition failed in reducing the synaptophysin loss induced by Abeta(1-40). The COX-2 upregulation induced by Abeta(1-40) was attributed to activation of different protein kinases and transcriptional factors that are greatly regulated by TNF-alpha. Together, these results indicate that Abeta(1-40) induces the activation of several TNF-alpha-dependent intracellular signaling pathways that play a key role in the control of COX-2 upregulation and activation, synaptic loss and cognitive decline in mice. Therefore, selective TNF-alpha inhibitors may be pote…
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Neuroinflammation plays a crucial role in the pathogenesis of AD.
“Together with the increased activation of microglia and astrocytes, as well as the elevated expression of IL-1β, IL-6, and TNF-α, these results further support the crucial role of neuroinflammation in the pathogenesis of AD.”
From AD-Like Neuropsychiatric Dysfunction in a Mice Model Induced by a Combination of High-Fat Diet and Intraperitoneal Injection of Streptozotocin (2024) · cites this paper as Medeiros et al., 2010
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- Authors
- Medeiros, R., Figueiredo, C. P., Pandolfo, P., Duarte, F. S., Prediger, R. D. S., Passos, G. F., & Calixto, J. B.
- Affiliations
- Universidade Federal de Santa Catarina (BR)
- ORCID
- Venue
- Behavioural Brain Research
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 209
- Issue
- 1
- Pages
- 165-173
- ISSN
- 0166-4328 (ISSN-L)
- OpenAlex
- W2071244560
- Cited by
- 121
- References
- 7
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 9 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 9 · 2019: 5 · 2018: 9 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 7 · 2013: 9 · 2012: 10
- FWCI
- 6.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Behavioural Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Universidade Federal de Santa Catarina
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, amyloid-beta, Aβ40, TNF signaling, cyclooxygenase-2, cognitive decline, synaptic loss, synaptophysin, neuroinflammation, protein kinases, transcription factors, TNF-alpha inhibitors, intracerebroventricular administration
- MeSH terms
- Analysis of Variance, Animals, Antibodies, Cognition Disorders, Disease Models, Animal, Enzyme Inhibitors, Hippocampus, Mice, Inbred C57BL, Nitrobenzenes, Peptide Fragments, Protein Kinase C, Sulfonamides, Tumor Necrosis Factor-alpha, Dinoprostone, Signal Transduction, Up-Regulation, Amyloid beta-Peptides, Mice, Knockout, Maze Learning, Recognition, Psychology, Electrophoretic Mobility Shift Assay, Receptors, Tumor Necrosis Factor, Type I, CREB-Binding Protein, Mice, Cyclooxygenase 2
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