NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42.
Beta-amyloid (Abeta) peptides that accumulate in Alzheimer disease are generated from the beta-amyloid precursor protein (betaAPP) by cleavages by beta-secretase BACE1 and by presenilin-dependent gamma-secretase activities. Very few data document a putative cross-talk between these proteases and the regulatory mechanisms underlying such interaction. We show that presenilin deficiency lowers BACE1 maturation and affects both BACE1 activity and promoter transactivation. The specific gamma-secretase inhibitor DFK167 triggers the decrease of BACE1 activity in wild-type but not in presenilin-deficient fibroblasts. This decrease is also elicited by catalytically inactive gamma-secretase. The overexpression of APP intracellular domain (AICD), the gamma/epsilon-secretase-derived C-terminal product of beta-amyloid precursor protein, does not modulate BACE1 activity or promoter transactivation in fibroblasts and does not alter BACE1 expression in AICD transgenic brains of mice. A DFK167-sensitive increase of BACE1 activity is observed in cells overexpressing APPepsilon (the N-terminal product of betaAPP generated by epsilon-secretase cleavage harboring the Abeta domain but lacking the AICD sequence), suggesting that the production of Abeta could account for the modulation of BACE1. Accordingly, we show that HEK293 cells overexpressing wild-type betaAPP exhibit a DFK167-sensitive increase in BACE1 promoter transactivation that is increased by the Abeta-potentiating Swedish mutation. This effect was mimicked by exogenous application of Abeta42 but not Abeta40 or by transient transfection of cDNA encoding Abeta42 sequence. The IkappaB kinase inhibitor BMS345541 prevents Abeta-induced BACE1 promoter transactivation suggesting that NFkappaB could mediate this Abeta-associated phenotype. Accordingly, the overexpression of wild-type or Swedish mutated betaAPP does not modify the transactivation of BACE1 promoter constructs lacking NFkappaB-responsive element. Furthermore, APP/beta-amyloid precursor protein-like protein deficiency does not affect BACE1 activity and expression. Overall, these data suggest that physiological levels of endogenous Abeta are not sufficient per se to modulate BACE1 promoter transactivation but that exacerbated Abeta production linked to wild-type or Swedish mutated betaAPP overexpression modulates BACE1 promoter transactivation and activity via an NFkappaB-dependent pathway.
Buggia-Prevot
Virginie
V
Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097 CNRS/UNSA, Equipe Labellisée Fondation pour la Recherche Médicale, 06560 Valbonne, France.
Sevalle
Jean
J
Rossner
Steffen
S
Checler
Frédéric
F
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D016328:NF-kappa B; D053763:Presenilins; D011480:Protease Inhibitors; D051550:I-kappa B Kinase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse