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Alzheimer Aβ peptides induce dysregulation of C/EBP and NF-кB in glial cells
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
Ansvarig organisation
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: Institutionen för neurokemi , 2008. , s. 124
Nyckelord [en]
Alzheimer's disease, amyloid-β, astrocytes, C/EBP, glia, microglia, neuroinflammation, NF-кB
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
neurokemi och neurotoxikologi
Identifikatorer
URN: urn:nbn:se:su:diva-7968ISBN: 978-91-7155-682-0 (tryckt)OAI: oai:DiVA.org:su-7968DiVA, id: diva2:199368
Disputation
2008-09-26, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Handledare
Tillgänglig från: 2008-09-04 Skapad: 2008-09-02 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Delarbeten
1. Alzheimer amyloid-beta peptides block the activation of C/EBP beta and C/EBP delta in glial cells
Öppna denna publikation i ny flik eller fönster >>Alzheimer amyloid-beta peptides block the activation of C/EBP beta and C/EBP delta in glial cells
2008 (Engelska)Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 370, nr 4, s. 619-622Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Alzheimer's disease, amyloid-beta, C/EBP, Glia, neuroinflammation
Nationell ämneskategori
Biokemi och molekylärbiologi Biofysik
Identifikatorer
urn:nbn:se:su:diva-25295 (URN)10.1016/j.bbrc.2008.03.150 (DOI)000255883900018 ()
Tillgänglig från: 2008-09-04 Skapad: 2008-09-02 Senast uppdaterad: 2022-02-25Bibliografiskt granskad
2. Alzheimer Aβ peptides induce кB binding complexes containing C/EBPδ
Öppna denna publikation i ny flik eller fönster >>Alzheimer Aβ peptides induce кB binding complexes containing C/EBPδ
(Engelska)Manuskript (Övrigt vetenskapligt)
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-25296 (URN)
Tillgänglig från: 2008-09-04 Skapad: 2008-09-02 Senast uppdaterad: 2022-02-25Bibliografiskt granskad
3. β-Amyloid and interleukin-1β induce persistent NF-κB activation in rat primary glial cells
Öppna denna publikation i ny flik eller fönster >>β-Amyloid and interleukin-1β induce persistent NF-κB activation in rat primary glial cells
2005 (Engelska)Ingår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 16, nr 3, s. 449-453Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-25297 (URN)10.3892/ijmm.16.3.449 (DOI)
Tillgänglig från: 2008-09-04 Skapad: 2008-09-02 Senast uppdaterad: 2022-02-25Bibliografiskt granskad
4. Targeting cytokine expression in glial cells by cellular delivery of an NFκB decoy
Öppna denna publikation i ny flik eller fönster >>Targeting cytokine expression in glial cells by cellular delivery of an NFκB decoy
Visa övriga...
2007 (Engelska)Ingår i: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 31, nr 3, s. 209-219Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Inhibition of nuclear factor (NF)-κB has emerged as an important strategy for design of anti-inflammatory therapies. In neurodegenerative disorders like Alzheimer’s disease, inflammatory reactions mediated by glial cells are believed to promote disease progression. Here, we report that uptake of a double-stranded oligonucleotide NF-κB decoy in rat primary glial cells is clearly facilitated by noncovalent binding to a cell-penetrating peptide, transportan 10, via a complementary peptide nucleic acid (PNA) sequence. Fluorescently labeled oligonucleotide decoy was detected in the cells within 1 h only when cells were incubated with the decoy in the presence of cell-penetrating peptide. Cellular delivery of the decoy also inhibited effects induced by a neurotoxic fragment of the Alzheimer β amyloid peptide in the presence of the inflammatory cytokine interleukin (IL) 1β. Pretreatment of the cells with the complex formed by the decoy and the cell-penetrating peptide-PNA resulted in 80% and 50% inhibition of the NF-κB binding activity and IL-6 mRNA expression, respectively.

Nyckelord
β-amyloid, astrocytes, cell-penetrating peptide, inflammation, nuclear factor-κB, peptide nucleic acid
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
biokemi; neurokemi och neurotoxikologi
Identifikatorer
urn:nbn:se:su:diva-25921 (URN)10.1385/JMN:31:03:209 (DOI)000246588800003 ()
Tillgänglig från: 2006-05-18 Skapad: 2006-05-18 Senast uppdaterad: 2022-02-25Bibliografiskt granskad

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