Nuclear Factor-κB Regulates βAPP and β- and γ-Secretases Differently at Physiological and Supraphysiological Aβ Concentrations

Abstract

Anatomical lesions in Alzheimer disease-affected brains mainly consist of senile plaques, inflammation stigmata, and oxidative stress. The nuclear factor-κB (NF-κB) is a stress-activated transcription factor that is activated around senile plaques. We have assessed whether NF-κB could be differentially regulated at physiological or supraphysiological levels of amyloid β (Aβ) peptides. Under these experimental conditions, we delineated the putative NF-κB-dependent modulation of all cellular participants in Aβ production, namely its precursor βAPP (β-amyloid precursor protein) and the β- and γ-secretases, the two enzymatic machines involved in Aβ genesis. Under physiological conditions, NF-κB lowers the transcriptional activity of the promoters of βAPP, β-secretase (β-site APP-cleaving enzyme 1, BACE1), and of the four protein components (Aph-1, Pen-2, nicastrin, presenilin-1, or presenilin-2) of the γ-secretase in HEK293 cells. This was accompanied by a reduction of both protein levels and enzymatic activities, thereby ultimately yielding lower amounts of Aβ and AICD (APP intracellular domain). In stably transfected Swedish βAPP-expressing HEK293 cells triggering supraphysiological concentrations of Aβ peptides, NF-κB activates the transcription of βAPP, BACE1, and some of the γ-secretase members and increases protein expression and enzymatic activities, resulting in enhanced Aβ production. Our pharmacological approach using distinct NF-κB kinase modulators indicates that both NF-κB canonical and alternative pathways are involved in the control of Aβ production. Overall, our data demonstrate that under physiological conditions, NF-κB triggers a repressive effect on Aβ production that contributes to maintaining its homeostasis, while NF-κB participates in a degenerative cycle where Aβ would feed its own production under pathological conditions.