Cyclic AMP Inhibition of Tumor Necrosis Factor α Production Induced by Amyloidogenic C-Terminal Peptide of Alzheimer's Amyloid Precursor Protein in Macrophages: Involvement of Multiple Intracellular Pathways and Cyclic AMP Response Element Binding Protein

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摘要：

In the present study, we focused on the molecular events involved in -alpha () production in response to the amyloidogenic 105-amino acid carboxyl-terminal fragment (CT105) of amyloid precursor protein, a candidate alternative toxic element in pathology, and the mechanisms by which cyclic regulates the relating inflammatory signal cascades. CT105 at nanomolar concentrations strongly activated multiple signaling pathways involving tyrosine kinase-dependent signal-regulated kinase and . Moreover, phosphatidylinositol 3-kinase/signal was required for excess production in macrophages derived from -1 cells. significantly potentiated the induction of the CT105-mediated signal cascade. These multiple signaling pathways in turn converged, at least in part, at the nuclear factor known as (), which acts on the gene promoter through the cAMP response element. The cell-permeable cAMP analog partially and almost simultaneously suppressed all of these CT105-induced signaling pathways through excessive , which led to decreased activity and reduced expression. Furthermore, decreased the interaction of the nuclear factor-kappa B with , thus further inhibiting CT105-mediated expression. Collectively, the detailed molecular mechanisms of amyloidogenic CT-induced production as negatively regulated by cAMP may advance the possibility of targeted treatment in .

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关键词：

Amyloid beta Protein Precursor Cyclic AMP DNA Binding Protein, Cyclic AMP Responsive Macrophages Tumor Necrosis Factor 1 Phosphatidylinositol 3 Kinase Alzheimer Disease Cells, Cultured DNA Macrophage Activation