Alzheimer A? peptides induce dysregulation of C/EBP and NF-?B in glial cells

Detta är en avhandling från Stockholm : Institutionen för neurokemi

Sammanfattning: Inflammation is believed to contribute to neurodegeneration in Alzheimer’s disease (AD). AD in turn is believed to be a consequence of accumulated amyloid-? (A?) peptides, that subsequently form senile plaques, due to imbalance between production and clearance of A?. 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 A? on C/EBP and NF-?B transcription factors in mixed primary glial cultures activated by inflammatory mediators. In addition, we investigated the possibility to block effects downstream of the ?B element with an NF-?B decoy coupled to a cell-penetrating peptide (CPP).Our results show that A? peptides blocked interleukin (IL)-1? induced activation of C/EBP? and C/EBP? whereas the effect on NF-?B was the opposite. Furthermore, we observed C/EBP? containing complexes binding to the ?B element only in the presence of A? peptides and IL-1?. In addition, NF-?B 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-?B decoy. In summary, dysregulation of C/EBP?, C/EBP? and NF-?B in response to A? peptides and inflammatory mediators support that the normal inflammatory response is disturbed in AD.

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