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Inflammatory cytokines and NFκB in Alzheimer’s disease
Stockholm University, Faculty of Science, Department of Neurochemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease is the most common form of dementia. It is a neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles. The main constituent of the senile plaques is the neurotoxic β-amyloid peptide. Surrounding the senile plaques are activated astrocytes and microglia, believed to contribute to neurotoxicity through secretion of proinflammatory cytokines, like interleukin-1β and interleukin-6. For many inflammatory actions, including the cytokine induction in glial cells, the transcription factor NFκB plays a key role. This suggests that therapeutical strategies aimed to control the development of Alzheimer’s disease could include administration of drugs that hinder NFκB activation.

The major aim of this thesis was to examine the effects of β-amyloid together with interleukin-1β on cytokine expression as well as NFκB activation in glial cells. The possibility to block NFκB activation, and downstream effects like interleukin-6 expression, by using an NFκB decoy was investigated. The possibility to improve the cellular uptake of the decoy by linking it to a cell-penetrating peptide was also investigated.

The results obtained provide supportive evidence that inflammatory cytokines are induced by β-amyloid, and that they can indeed potentiate its effects. The results further demonstrate that by blocking NFκB activation, the induction of interleukin-6 expression can be inhibited. By using an improved cellular delivery system, the uptake of the NFκB decoy and hence the downstream cytokine inhibition could be increased. In conclusion, these results demonstrate the possibility to decrease the inflammatory reactions taken place in Alzheimer’s disease brains, which may ultimately lead to a possible way of controlling this disorder.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi , 2006. , 130 p.
Keyword [en]
β-amyloid, interleukin-1, interleukin-6, cell-penetrating peptide, PNA
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:su:diva-990ISBN: 91-7155-265-0 (print)OAI: oai:DiVA.org:su-990DiVA: diva2:200804
Public defence
2006-06-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Opponent
Supervisors
Available from: 2006-05-18 Created: 2006-05-18Bibliographically approved
List of papers
1. Cellular delivery of a double-stranded oligonucleotide NFκB decoy by hybridization to complementary PNA linked to a cell-penetrating peptide
Open this publication in new window or tab >>Cellular delivery of a double-stranded oligonucleotide NFκB decoy by hybridization to complementary PNA linked to a cell-penetrating peptide
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2004 (English)In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 11, 1264-1272 p.Article in journal (Refereed) Published
Abstract [en]

The activation of nuclear factor B (NFB) is a key event in immune and inflammatory responses. In this study, a cell-penetrating transport peptide, transportan (TP) or its shorter analogue TP 10, was used to facilitate the cellular uptake of an NFB decoy. Peptide nucleic acid (PNA) hexamer or nonamer was linked to the transport peptide by a disulfide bond. NFB decoy oligonucleotide consisted of a double-stranded consensus sequence corresponding to the B site localized in the IL-6 gene promoter, 5'-GGGACTTTCCC-3', with a single-stranded protruding 3'-terminal sequence complementary to the PNA sequence was hybridized to the transport peptide–PNA construct. The ability of the transport peptide–PNA–NFB decoy complex to block the effect of interleukin (IL)-1-induced NFB activation and IL-6 gene expression was analyzed by electrophoretic mobility shift assay and reverse transcriptase-polymerase chain reaction in rat Rinm5F insulinoma cells. Preincubation with transport peptide–PNA–NFB decoy (1 M, 1 h) blocked IL-1-induced NFB-binding activity and significantly reduced the IL-6 mRNA expression. The same concentration of NFB decoy in the absence of transport peptide–PNA had no effect even after longer incubations. Our results showed that binding of the oligonucleotide NFB decoy to the nonamer PNA sequence resulted in a stable complex that was efficiently translocated across the plasma membrane.

Keyword
nuclear factor decoy, NFkappaB, PNA, transport peptide, interleukin-1beta, interleukin-6
National Category
Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:su:diva-25919 (URN)10.1038/sj.gt.3302291 (DOI)
Available from: 2006-05-18 Created: 2006-05-18 Last updated: 2017-12-13Bibliographically approved
2. Additive effects of amyloid β fragment and interleukin-1β on IL-6 secretion in rat primary glial cultures.
Open this publication in new window or tab >>Additive effects of amyloid β fragment and interleukin-1β on IL-6 secretion in rat primary glial cultures.
2002 In: International Journal of Molecular Medicine, ISSN 1107-3756, Vol. 10, 245-250 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25920 (URN)
Note
Part of urn:nbn:se:su:diva-990Available from: 2006-05-18 Created: 2006-05-18Bibliographically approved
3. Targeting cytokine expression in glial cells by cellular delivery of an NFκB decoy
Open this publication in new window or tab >>Targeting cytokine expression in glial cells by cellular delivery of an NFκB decoy
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2007 (English)In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 31, no 3, 209-219 p.Article in journal (Refereed) 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.

Keyword
β-amyloid, astrocytes, cell-penetrating peptide, inflammation, nuclear factor-κB, peptide nucleic acid
National Category
Biological Sciences
Research subject
Biochemistry; Neurochemistry and Neurotoxicology
Identifiers
urn:nbn:se:su:diva-25921 (URN)10.1385/JMN:31:03:209 (DOI)000246588800003 ()
Available from: 2006-05-18 Created: 2006-05-18 Last updated: 2017-12-13Bibliographically approved
4. Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in cultured rat primary neurons and astrocytes
Open this publication in new window or tab >>Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in cultured rat primary neurons and astrocytes
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2003 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 336, no 1, 55-59 p.Article in journal (Refereed) Published
Abstract [en]

The amyloid precursor protein (APP) and its proteolytic cleavage products, the amyloid P peptides, have been implicated as a cause of Alzheimer's disease. Peptide nucleic acids (PNA), the DNA mimics, have been shown to block the expression of specific proteins at both transcriptional and translational levels. Generally, the cellular uptake of PNA is low. However, recent studies have indicated that the effect of unmodified antisense PNA uptake is more pronounced in nervous tissue. In this study we have shown that biotinylated PNA directed to the initiator codon region of the APP mRNA (-4 - +11) was taken up into the cytoplasm of primary rat cerebellar granule cells and cortical astrocytes, using fluorescence and confocal microscopy studies. Uptake of PNA was faster in neurons than in astrocytes. Western blotting analysis showed that APP was strongly down-regulated in both neurons and astrocytes. Thus, unmodified PNA can be used for studies on the function of APP in neurons and astrocytes.

Keyword
Alzheimer's disease, amyloid precursor protein, antisense, cerebellar granule cells, peptide nucleic acid
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:su:diva-25922 (URN)10.1016/S0304-3940(02)01219-3 (DOI)000180433900014 ()
Available from: 2006-05-18 Created: 2006-05-18 Last updated: 2017-12-13Bibliographically approved

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