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Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in cultured rat primary neurons and astrocytes
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi. University of Tartu, Estonia.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi och neurotoxikologi.
Vise andre og tillknytning
2003 (engelsk)Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 336, nr 1, s. 55-59Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2003. Vol. 336, nr 1, s. 55-59
Emneord [en]
Alzheimer's disease, amyloid precursor protein, antisense, cerebellar granule cells, peptide nucleic acid
HSV kategori
Identifikatorer
URN: urn:nbn:se:su:diva-25922DOI: 10.1016/S0304-3940(02)01219-3ISI: 000180433900014OAI: oai:DiVA.org:su-25922DiVA, id: diva2:200803
Tilgjengelig fra: 2006-05-18 Laget: 2006-05-18 Sist oppdatert: 2018-01-13bibliografisk kontrollert
Inngår i avhandling
1. Inflammatory cytokines and NFκB in Alzheimer’s disease
Åpne denne publikasjonen i ny fane eller vindu >>Inflammatory cytokines and NFκB in Alzheimer’s disease
2006 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Institutionen för neurokemi, 2006. s. 130
Emneord
β-amyloid, interleukin-1, interleukin-6, cell-penetrating peptide, PNA
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-990 (URN)91-7155-265-0 (ISBN)
Disputas
2006-06-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Opponent
Veileder
Tilgjengelig fra: 2006-05-18 Laget: 2006-05-18 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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