title: Oligomers of β-amyloid protein (Aβ1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1β, tumour necrosis factor-α, and a nuclear factor κ-B mechanism in the rat brain.
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.
authors.affiliation: Laboratory of Neuroanatomy, Institute of Neuroscience of Castilla and León, Valladolid University (Campus of Soria), Spain.
authors.forename: I
authors.initials: I
authors.lastname: Carrero
authors.forename: M R
authors.initials: MR
authors.lastname: Gonzalo
authors.forename: B
authors.initials: B
authors.lastname: Martin
authors.forename: J M
authors.initials: JM
authors.lastname: Sanz-Anquela
authors.forename: J
authors.initials: J
authors.lastname: Arévalo-Serrano
authors.forename: A
authors.initials: A
authors.lastname: Gonzalo-Ruiz
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D018836:Inflammation Mediators / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology / Q000633:toxicity*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat