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The CCAAT/enhancer binding protein (C/EBP) δ is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-β peptide
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-6668-1094
Stockholm University, Faculty of Science, Department of Neurochemistry.
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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) α, β and δ have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor κB (NF-κB). In general, C/EBPα is down-regulated, whereas both C/EBPβ and δ 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-β (Aβ) 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 Aβ deposits with the aim of defining new therapeutic targets.

METHODS:

Here we have investigated the effects of Aβ on expression of C/EBP family members with a focus on C/EBPδ in rat primary astro-microglial cultures and in a transgenic mouse model with high levels of fibrillar Aβ deposits (tg-ArcSwe) by western blot analysis. Effects on DNA binding activity were analyzed by electrophoretic mobility shift assay. Cross-talk between C/EBPδ and NF-κB was investigated by analyzing binding to a κB site using a biotin streptavidin-agarose pull-down assay.

RESULTS:

We show that exposure to fibril-enriched, but not oligomer-enriched, preparations of Aβ inhibit up-regulation of C/EBPδ expression in interleukin-1β-activated glial cultures. Furthermore, we observed that, in aged transgenic mice, C/EBPα was significantly down-regulated and C/EBPβ was significantly up-regulated. C/EBPδ, on the other hand, was selectively down-regulated in the forebrain, a part of the brain showing high levels of fibrillar Aβ deposits. In contrast, no difference in expression levels of C/EBPδ between wild type and transgenic mice was detected in the relatively spared hindbrain. Finally, we show that interleukin-1β-induced C/EBPδ DNA binding activity to both C/EBP and κB sites is abolished after exposure to Aβ.

CONCLUSIONS:

These data suggest that both expression and function of C/EBPδ are dysregulated in Alzheimer's disease. C/EBPδ seems to be differently regulated in response to different conformations of Aβ. We propose that Aβ induces an imbalance between NF-κB 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
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-58649DOI: 10.1186/1742-2094-8-34ISI: 000290687600001PubMedID: 21492414OAI: oai:DiVA.org:su-58649DiVA: diva2:421098
Available from: 2011-06-07 Created: 2011-06-07 Last updated: 2015-03-16Bibliographically approved
In thesis
1. Neuroinflammation in Alzheimer's disease: Focus on NF-κB and C/EBP transcription factors
Open this publication in new window or tab >>Neuroinflammation in Alzheimer's disease: Focus on NF-κB and C/EBP transcription factors
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer's disease (AD) is the most common form of dementia among elderly. The disease is characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, loss of synapses and neurons and chronic neuroinflammation. The significance of neuroinflammatory processes in disease on-set and progression has been debated since activated microglia and reactive astrocytes have been attributed both protective and damaging properties. However, patients systematically treated with anti-inflammatory drugs have been shown to develop AD to a lesser extent than average. This indicates an important role of neuroinflammation in AD.

This thesis focuses on two inflammatory related transcription factors, nuclear factor κB (NF-κB) and CCAAT/enhancer binding protein (C/EBP). Both NF-κB and C/EBP are known regulators of many pro-inflammatory genes and may during certain circumstances dimerize with each other.

In paper I we use a new strategy to inhibit NF-κB DNA binding activity in primary astro-microglial cell cultures treated with Aβ and IL-1β. By coupling the NF-κB decoy to a transport peptide both concentration and incubation time can be shortened in comparison to previous studies. Moreover, using the same in vitro model in paper II and III, we show members of the C/EBP family to be dysregulated during AD mimicking conditions. Additional focus was directed towards C/EBPδ, which was shown to respond differently to oligomeric and fibrillar forms of Aβ. Results were also confirmed in vivo using an AD mouse model characterized by high levels of fibrillar Aβ deposits. Finally, in order to get further insight in neurodegenerative processes, induced by Aβ or microglial activation, we present in paper IV a new set of anchored sensors for detection of locally activated caspases in neuronal cells. By anchoring the sensors to tau they become less dynamic and caspase activation can be detected early on in the apoptotic process, in a spatio-temporal and reproducible manner.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2011. 65 p.
Keyword
Alzheimer’s disease, neuroinflammation, NF-κB, C/EBP, apoptosis, caspases, FRET
National Category
Natural Sciences
Research subject
Neurochemistry and Neurotoxicology
Identifiers
urn:nbn:se:su:diva-62492 (URN)978-91-7447-356-8 (ISBN)
Public defence
2011-10-28, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2011-10-06 Created: 2011-09-21 Last updated: 2011-09-21Bibliographically approved
2. Neuroinflammation in Alzheimer’s disease and obesity
Open this publication in new window or tab >>Neuroinflammation in Alzheimer’s disease and obesity
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) and obesity are both major problems in the western world. Although they may appear to have little in common at first glance, they are both characterized by chronic inflammation. Exactly how inflammation affects these disorders is far from clear. Microglia, the resident immune cells of the brain, can take on different phenotypes in response to inflammatory stimuli. They can become classically or alternatively activated, where they secrete pro- or anti-inflammatory cytokines respectively. The inflammatory response is to a large part regulated by transcription factors, such as C/EBPδ, which regulate gene expression. The aim of this thesis was to investigate 1) effects of the Alzheimer’s related peptide amyloid-β (Aβ) on C/EBPδ in astrocytes and microglia during inflammatory conditions, 2) how microglia is affected by elevated levels of free fatty acids (FFAs) occurring in obesity and 3) possible cellular sources of the neuroprotective peptide GLP-1 in the brain. In paper I we found that IL-1β-induced C/EBPδ appears to be blocked by Aβ fibrils but not Aβ oligomers in mixed glial cells. In paper II we found that the decreased levels of C/EBPδ were limited to astrocytes under inflammatory conditions and that there was no blocking of IL-1β-induced C/EBPδ in microglia. In paper III we found that the FFA palmitate induces an alternative activation in microglia with no effect on the expression of C/EBPδ or the pro-inflammatory cytokines TNF-α, IL-1β and IL-6. However, pre-exposure to palmitate potentiated microglia phagocytosis and changed the mRNA expression profile of some pro-inflammatory cytokines in response to inflammatory stimuli. In paper IV we found microglia to be a novel source of secreted GLP-1. Further, we found that the GLP-1 secretion could be decreased by inflammatory stimuli. In summary, the inflammatory response of C/EBPδ in AD appears to be disturbed. In addition, palmitate affects the response to inflammatory stimuli in microglia.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2013. 56 p.
Keyword
Alzheimer's disease, obesity, neuroinflammation
National Category
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-95104 (URN)978-91-7447-731-3 (ISBN)
Public defence
2013-11-22, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.

Available from: 2013-10-31 Created: 2013-10-21 Last updated: 2015-03-16Bibliographically approved

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Ramberg, VeronicaTracy, LindaIverfeldt, Kerstin
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