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Alzheimer amyloid-beta peptides block the activation of C/EBP beta and C/EBP delta in glial cells
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-0308-1964
Responsible organisation
2008 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 370, no 4, 619-622 p.Article in journal (Refereed) Published
Abstract [en]

Members of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors have been reported to be up-regulated in Alzheimer's disease. In the present study, we have investigated the effects of amyloid-beta (A beta) peptides on C/EBP beta and C/EBP delta, previously shown to be induced by inflammatory stimuli in glial cells. Surprisingly, electrophoretic mobility shift assay showed that both A beta(1-42) and A beta(25-35) blocked C/EBP activation induced by the inflammatory cytokine interleukin-1 (IL-1 beta) or lipopolysac-charicle (LPS) in mixed primary glial cell cultures from rat. A beta also blocked IL-1 or LPS-incluced C/EBP protein levels. The most prominent effects were observed on DNA binding activity and protein levels of C/EBP delta. Our results demonstrate a dysregulation of C/EBP when glial cells are activated in the presence of Alzheimer A beta peptides.

Place, publisher, year, edition, pages
2008. Vol. 370, no 4, 619-622 p.
Keyword [en]
Alzheimer's disease, amyloid-beta, C/EBP, Glia, neuroinflammation
National Category
Biochemistry and Molecular Biology Biophysics
Identifiers
URN: urn:nbn:se:su:diva-25295DOI: 10.1016/j.bbrc.2008.03.150ISI: 000255883900018OAI: oai:DiVA.org:su-25295DiVA: diva2:199364
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.
Keyword
Alzheimer's disease, amyloid-β, astrocytes, C/EBP, glia, microglia, neuroinflammation, NF-кB
National Category
Neurosciences
Research subject
Neurochemistry and Neurotoxicology
Identifiers
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
Opponent
Supervisors
Available from: 2008-09-04 Created: 2008-09-02 Last updated: 2011-09-21Bibliographically approved
2. 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

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