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-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.
Équipe Labellisée "Fondation pour la Recherche Médicale" and "Excellence Laboratory Distalz", Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, 660 Route des Lucioles, 06560, Valbonne, France.
Linda
L
Chami
Virginie
V
Buggia-Prévot
Eric
E
Duplan
Dolores
D
Del Prete
Dolores
D
Delprete
Mounia
M
Chami
Jean-François
JF
Peyron
Frédéric
F
Checler
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human