The Transcriptional Activity of the APP Intracellular Domain−Fe65 Complex Is Inhibited by Activation of the NF-κB Pathway

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Abstract
The β-amyloid precursor protein (APP) is an integral membrane protein that is the subject of proteolytic processing. Sequential cleavage of APP by β-secretase and subsequently γ-secretase generates the β-amyloid peptide as well as a cytoplasmic intracellular domain (AICD). AICD binds to the transcriptional coactivator Fe65, and this complex has been shown to display transcriptional activity. The regulation of this complex is poorly understood. We show here that activation of the NF-κB pathway, either by overexpression of NF-κB-inducing kinase (NIK) or by treatment with the proinflammatory cytokine IL-1β, downregulates the transcriptional activity of the AICD−Fe65 complex. This therefore provides a mechanism by which the activity of AICD might be modulated by extracellular stimuli. These results also identify an intracellular signal transduction pathway influenced by the NF-κB signaling pathway.