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β-Amyloid and interleukin-1β induce persistent NF-κB activation in rat primary glial cells
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.ORCID iD: 0000-0002-0308-1964
Responsible organisation
2005 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 16, no 3, 449-453 p.Article in journal (Refereed) Published
Abstract [en]

An increasing body of evidence suggests that β-amyloid (Aβ) and activated glial cells play a crucial part in the pathogenesis of Alzheimer's disease (AD). Activated glial cells surrounding the senile plaques, formed by Aβ peptides, have been proposed to promote neurodegeneration by producing putatively toxic factors, including the inflammatory cytokine interleukin-1β (IL-1β). Elevated levels of both IL-1β and activated nuclear factor κB (NF-κB), a key transcription factor regulating a wide variety of inflammatory genes, have been found in the brains of AD patients. In this study, we have investigated the ability of the Aβ(25-35) peptide and IL-1β, either alone or together, in activating NF-κB in glial cells. Mixed primary glial cells from rat were treated with IL-1β and/or Aβ(25-35), and NF-κB binding activity was analyzed by electophoretic mobility shift assay. We observed that the induction of NF-κB binding activity induced by either IL-1β or Aβ(25-35) showed a peak at 30 min, and significantly declined after 2 h. The induced NF-κB activation persisted after 24 h and even seemed to increase in cells treated with Aβ(25-35). The activation of NF-κB by Aβ(25-35) was shown to be dose-dependent. In addition, Aβ(25-35) potentiated the effect of IL-1β in a dose-dependent manner when co-stimulating the cells. The potentiating effect of Aβ(25-35) on IL-1β-induced NF-κB binding activity was observed after 30 min, 2 h and 24 h, and did not significantly differ over time. A possible explanation is that when glial cells are stimulated by inflammatory factors in the presence of Aβ peptides or senile plaques, the NF-κB negative feedback regulation is no longer functional.

Place, publisher, year, edition, pages
2005. Vol. 16, no 3, 449-453 p.
National Category
Cell and Molecular Biology
URN: urn:nbn:se:su:diva-25297DOI: 10.3892/ijmm.16.3.449OAI: diva2:199366
Available from: 2008-09-04 Created: 2008-09-02 Last updated: 2015-03-09Bibliographically approved
In thesis
1. Alzheimer Aβ peptides induce dysregulation of C/EBP and NF-кB in glial cells
Open this publication in new window or tab >>Alzheimer Aβ peptides induce dysregulation of C/EBP and NF-кB in glial cells
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inflammation is believed to contribute to neurodegeneration in Alzheimer’s disease (AD). AD in turn is believed to be a consequence of accumulated amyloid-β (Aβ) peptides, that subsequently form senile plaques, due to imbalance between production and clearance of Aβ. Senile plaques are associated with dystrophic neurites, activated glia and various pro-inflammatory molecules. Microglia and astrocytes become activated to repair damage and kill intruders. There is a dramatic change in gene expression upon activation leading to production of pro-inflammatory and cytotoxic molecules. However in AD, glial cells fail to eliminate the disturbing agent and inflammation becomes chronic. Gene expression of putatively neurotoxic factors is under the control of various transcription factors. To find ways to increase beneficial effects of inflammation (phagocytosis of plaques) and dampen detrimental effects (production of neurotoxic molecules) it is important to understand how transcription factors responsible for these processes are regulated.

The aim of this thesis was to investigate the effects of Aβ on C/EBP and NF-кB transcription factors in mixed primary glial cultures activated by inflammatory mediators. In addition, we investigated the possibility to block effects downstream of the кB element with an NF-кB decoy coupled to a cell-penetrating peptide (CPP).

Our results show that Aβ peptides blocked interleukin (IL)-1β induced activation of C/EBPβ and C/EBPδ whereas the effect on NF-кB was the opposite. Furthermore, we observed C/EBPδ containing complexes binding to the кB element only in the presence of Aβ peptides and IL-1β. In addition, NF-кB p65 was found in complexes binding to the C/EBP site under all conditions. Lastly, we could block IL-6 mRNA expression levels to 50% using a CPP-NF-кB decoy. In summary, dysregulation of C/EBPβ, C/EBPδ and NF-кB in response to Aβ peptides and inflammatory mediators support that the normal inflammatory response is disturbed in AD.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2008. 124 p.
Alzheimer's disease, amyloid-β, astrocytes, C/EBP, glia, microglia, neuroinflammation, NF-кB
National Category
Research subject
Neurochemistry and Neurotoxicology
urn:nbn:se:su:diva-7968 (URN)978-91-7155-682-0 (ISBN)
Public defence
2008-09-26, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Available from: 2008-09-04 Created: 2008-09-02 Last updated: 2011-09-21Bibliographically approved

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Iverfeldt, Kerstin
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