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Transcription factors as targets to block inflammation in neurodegenerative disorder: s
Stockholm University.
Stockholm University.
Stockholm University.
Stockholm University.
Vise andre og tillknytning
2006 (engelsk)Inngår i: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 2, nr 3, Supplement, s. S457-Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
Abstract [en]

Background: Accumulating evidence supports the importance of inflammation in neurodegenerative disorders like Alzheimer’s disease (AD). Epidemiological studies have revealed that patients taking anti-inflammatory drugs for conditions like arthritis have a lower prevalence of Alzheimer’s than others. In addition, there are reports that show that inflammation indeed can cause neurodegeneration in vivo. “The glial loop hypothesis” describes the model where surrounding glial cells are activated and produce neurotoxic products and therefore lead to neuronal death. One of the most important transcription factors involved in the inflammatory signalling cascade is NF-κB (nuclear factor κB). Supporting a role for NF-κB in AD, this transcription factor has been shown to be upregulated in brains from patients suffering from the disease. Another transcription factor family, thought to work together with NF-κB, is CCAAT enhancer binding protein (C/EBP). C/EBPδ has also been shown to be overexpressed in brains from Alzheimer patients. 

Objective: Our aim was to characterize the activation of transcription factors that may be involved in AD and to investigate the possibilities to block the effects of these transcription factors. 

Methods: We have used a delivery system that we have previously developed with a decoy non-covalently bound to a cell-penetrating peptide (CPP). In our studies primary mixed glial cultures from rat (5-10% microglia and 90-95% astrocytes) were used as a modelsystem. Transcription factor activation and cytokine mRNA expression were analyzed by electrophoretic mobility shift assay and RT-PCR, respectively. Cellular uptake studies were performed using confocal laser scanning microscopy. 

Results: Our studies show that a β-amyloid peptide alone or in combination with the inflammatory cytokine interleukin-1β upregulates NF-κB binding activity as well as the mRNA expression of its downstream target gene interleukin-6 (IL-6). Using our delivery system with an NF-κB decoy resulted in inhibition of upregulated NF-κB binding activity by approx. 80% and IL-6 mRNA expression by approx. 50%. We observed a clear uptake of the CPP-coupled decoy. In parallel, we have also investigated the possibility to use C/EBP as a therapeutic target. 

Conclusion: Facilitated uptake of transcription factor decoys may be a promising strategy to target the inflammation in neurodegenerative disorders like AD.

sted, utgiver, år, opplag, sider
2006. Vol. 2, nr 3, Supplement, s. S457-
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URN: urn:nbn:se:sh:diva-35288DOI: 10.1016/j.jalz.2006.05.1547OAI: oai:DiVA.org:sh-35288DiVA, id: diva2:1220735
Tilgjengelig fra: 2018-06-19 Laget: 2018-06-19 Sist oppdatert: 2023-03-28bibliografisk kontrollert

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