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Cited by 132Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsInflammatory mediators and NSAID effects

Oligomers of beta-amyloid protein (Aβ1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain

Carrero, I., Gonzalo, M.R., Martin, B., Sanz-Anquela, J.M., Arévalo-Serrano, J., Gonzalo-Ruiz, A.·2012·Experimental Neurology
DOI 10.1016/j.expneurol.2012.05.004
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Abstract

Despite growing evidence indicating the effects of cytokines, including interleukin-1beta (IL-1β) and tumour necrosis factor-α (TNFα), and the enzyme cyclooxygenase-2 (COX-2) in Alzheimer's diseases, little is known about the signalling mechanisms that mediate its activation in response to beta-amyloid protein (Aβ). The aim of this study was first to investigate whether Aβ1-42 peptide induced the up-regulation of COX-2. We then examined the expression of COX-2 and cytokines, such as IL-1β and TNFα, in reactive astrocytes. Finally, we analyzed the role of nuclear factor kappa-B (NF-κB) as a signalling pathway in early stages of Aβ-toxicity. In Wistar rats anaesthetised with equitesine, a single microinjection of Aβ1-42 oligomers was made in the left retrosplenial cortex. Control animals were injected with Aβ42-1 peptide into the corresponding region of the cerebral cortex. By COX-2 immunoblotting, we detected two immunopositive protein bands, at 70 and 50 kDa molecular mass. In the Aβ1-42-injected animals the 50 kDa fragment showed a significant increase at 3 and 14 days, as compared with that seen in control animals. The 70 kDa fragment showed a maximal increase at 14 days. In the Aβ1-42-injected animals immunoblot staining of NF-κB detected an active protein band at 50 kDa molecular mass, showing a maximal increase at the 72 h time point. Confocal analysis revealed that COX-2 protein co-localized with Aβ-IR material at the injection site and in endothelial blood vessels, increasing at 72 h. In the Aβ oligomer-treated animals, COX-2, IL-1β, and TNFα proteins were expressed in reactive astrocytes surrounding the injection site and blood vessels at early stages of Aβ toxicity. Double-labelling immunofluorescence studies also revealed that GFAP and COX-2 proteins co-localized with NF-κB-positive material at early time-points. In conclusion, our results suggest that in reactive astrocytes and in COX-2 positive cells NF-κB may mediate pro-, and/or inflammatory gene expression and that, develop strategies that target the GFAP/NF-κB and COX-2/NF-κB pathways might contribute to reducing Aβ-induced toxicity.

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Authors
Carrero, I., Gonzalo, M. R., Martin, B., Sanz-Anquela, J. M., Arévalo-Serrano, J., & Gonzalo-Ruiz, A.
Affiliations
Universidad de Valladolid (ES)
ORCID
Carrero, I.
Venue
Experimental Neurology
Publisher
Elsevier BV
Published
2012-08
Volume
236
Issue
2
Pages
215-227
ISSN
0014-4886 (ISSN-L)
DOI
10.1016/j.expneurol.2012.05.004
OpenAlex
W2119820996
Cited by
132
References
73
Citations by year
2026: 7 · 2025: 3 · 2024: 11 · 2023: 12 · 2022: 5 · 2021: 14 · 2020: 9 · 2019: 9 · 2018: 12 · 2017: 11 · 2016: 6 · 2015: 12 · 2014: 12 · 2013: 6 · 2012: 2
FWCI
6.86
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Experimental Neurology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Junta de Castilla and León (VA017A10-2)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
Keywords
amyloid-beta oligomers, amyloid-beta 42, cyclooxygenase-2, astrocytes, IL-1β, TNF-α, NF-κB, Alzheimer's disease, neuroinflammation, reactive astrocytes, glial fibrillary acidic protein, amyloid toxicity, microinjection, retrosplenial cortex, blood vessels
MeSH terms
Animals, Astrocytes, Brain Chemistry, Enzyme Activation, Female, Peptide Fragments, Protein Binding, Tumor Necrosis Factor-alpha, Amyloid beta-Peptides, NF-kappa B, Rats, Wistar, Inflammation Mediators, Rats, Cyclooxygenase 2, Interleukin-1beta

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