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

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