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The CCAAT/enhancer binding protein (C/EBP) delta is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-beta peptide
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2011 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, Vol. 8, 34- p.Article in journal (Refereed) Published
Abstract [en]

Background: The transcription factors CCAAT/enhancer binding proteins (C/EBP) alpha, beta and delta have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor kappa B (NF-kappa B). In general, C/EBP alpha is down-regulated, whereas both C/EBP beta and delta are up-regulated in response to inflammatory stimuli. In Alzheimer's disease (AD) one of the hallmarks is chronic neuroinflammation mediated by astrocytes and microglial cells, most likely induced by the formation of amyloid-beta (A beta) deposits. The inflammatory response in AD has been ascribed both beneficial and detrimental roles. It is therefore important to delineate the inflammatory mediators and signaling pathways affected by Ab deposits with the aim of defining new therapeutic targets. Methods: Here we have investigated the effects of A beta on expression of C/EBP family members with a focus on C/EBP delta in rat primary astro-microglial cultures and in a transgenic mouse model with high levels of fibrillar A beta deposits (tg-ArcSwe) by western blot analysis. Effects on DNA binding activity were analyzed by electrophoretic mobility shift assay. Cross-talk between C/EBP delta and NF-kappa B was investigated by analyzing binding to a kappa B site using a biotin streptavidin-agarose pull-down assay. Results: We show that exposure to fibril-enriched, but not oligomer-enriched, preparations of A beta inhibit upregulation of C/EBP delta expression in interleukin-1 beta-activated glial cultures. Furthermore, we observed that, in aged transgenic mice, C/EBP alpha was significantly down-regulated and C/EBP beta was significantly up-regulated. C/EBP beta, on the other hand, was selectively down-regulated in the forebrain, a part of the brain showing high levels of fibrillar A beta deposits. In contrast, no difference in expression levels of C/EBP delta between wild type and transgenic mice was detected in the relatively spared hindbrain. Finally, we show that interleukin-1 beta-induced C/EBP delta DNA binding activity to both C/EBP and kappa B sites is abolished after exposure to A beta. Conclusions: These data suggest that both expression and function of C/EBP delta are dysregulated in Alzheimer's disease. C/EBP delta seems to be differently regulated in response to different conformations of A beta. We propose that A beta induces an imbalance between NF-kappa B and C/EBP transcription factors that may result in abnormal responses to inflammatory stimuli.

Place, publisher, year, edition, pages
2011. Vol. 8, 34- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-154601DOI: 10.1186/1742-2094-8-34ISI: 000290687600001PubMedID: 21492414OAI: oai:DiVA.org:uu-154601DiVA: diva2:421570
Available from: 2011-06-09 Created: 2011-06-08 Last updated: 2011-06-09Bibliographically approved

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