Oxidative mechanisms in London Familial Alzheimer´s disease and LPS-induced inflammation
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Alzheimer´s disease (AD) is the most common of the progressive neurodegenerative disorders and is characterized by the formation of Aβ deposits, neurofibrillary tangles and loss of neurons. Additional features of the disease are inflammation, increased oxidative stress and modified iron metabolism.
One aim of the thesis was to study the London mutation of the amyloid precursor protein (APP) gene, and the potential role of this mutation in oxidative mechanisms regulating G-protein activity and cytotoxicity. A second aim was to investigate the relative influence of reactive oxygen species (ROS) and nitric oxide (NO) species on iron metabolism in cell lines exposed to lipopolysaccharide (LPS). Additionally, the impact of the intracellular redox environment on inducible NO synthase (iNOS) regulation in activated microglia was examined.
The results show that the wild-type APP(714-723) peptide stimulated G-protein activity in human brain membranes by a mechanism that was independent of free radical formation. Compared to the wild-type peptide, the London mutated V717G-APP(714-723) was a more powerful stimulator of G-protein activity. This activation involved a free radical mechanism that was dependent on the V717G mutation and the oxidation state of Met722. The exposure of N2a and BV-2 cells to LPS resulted in increased H-ferritin mRNA levels, an increase that was found to be independent of LPS-induced ROS and NO formation. TfR protein levels were decreased by the treatment and were shown to be regulated by ROS and NO species. Co-exposure of BV-2 cells to LPS and antioxidants resulted in increased iNOS protein levels as compared to LPS exposure alone. The results further indicate that the increase of iNOS protein levels was dependent on a regulatory mechanism involving the p38 MAPK pathway.
Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi , 2007. , 79 p.
Research subject Neurochemistry and Molecular Neurobiology
IdentifiersURN: urn:nbn:se:su:diva-6824ISBN: 978-91-7155-419-2OAI: oai:DiVA.org:su-6824DiVA: diva2:197130
2007-06-08, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
de Sousa, Maria, Professor
Land, Tiit, Docent
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