NFκB-dependent Control of BACE1 Promoter Transactivation by Aβ42

β-Amyloid (Aβ) peptides that accumulate in Alzheimer disease are generated from the β-amyloid precursor protein (βAPP) by cleavages by β-secretase BACE1 and by presenilin-dependent γ-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 γ-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 γ-secretase. The overexpression of APP intracellular domain (AICD), the γ/ϵ-secretase-derived C-terminal product of β-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 APPϵ (the N-terminal product of βAPP generated by ϵ-secretase cleavage harboring the Aβ domain but lacking the AICD sequence), suggesting that the production of Aβ could account for the modulation of BACE1. Accordingly, we show that HEK293 cells overexpressing wild-type βAPP exhibit a DFK167-sensitive increase in BACE1 promoter transactivation that is increased by the Aβ-potentiating Swedish mutation. This effect was mimicked by exogenous application of Aβ42 but not Aβ40 or by transient transfection of cDNA encoding Aβ42 sequence. The IκB kinase inhibitor BMS345541 prevents Aβ-induced BACE1 promoter transactivation suggesting that NFκB could mediate this Aβ-associated phenotype. Accordingly, the overexpression of wild-type or Swedish mutated βAPP does not modify the transactivation of BACE1 promoter constructs lacking NFκB-responsive element. Furthermore, APP/β-amyloid precursor protein-like protein deficiency does not affect BACE1 activity and expression. Overall, these data suggest that physiological levels of endogenous Aβ are not sufficient per se to modulate BACE1 promoter transactivation but that exacerbated Aβ production linked to wild-type or Swedish mutated βAPP overexpression modulates BACE1 promoter transactivation and activity via an NFκB-dependent pathway. β-Amyloid (Aβ) peptides that accumulate in Alzheimer disease are generated from the β-amyloid precursor protein (βAPP) by cleavages by β-secretase BACE1 and by presenilin-dependent γ-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 γ-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 γ-secretase. The overexpression of APP intracellular domain (AICD), the γ/ϵ-secretase-derived C-terminal product of β-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 APPϵ (the N-terminal product of βAPP generated by ϵ-secretase cleavage harboring the Aβ domain but lacking the AICD sequence), suggesting that the production of Aβ could account for the modulation of BACE1. Accordingly, we show that HEK293 cells overexpressing wild-type βAPP exhibit a DFK167-sensitive increase in BACE1 promoter transactivation that is increased by the Aβ-potentiating Swedish mutation. This effect was mimicked by exogenous application of Aβ42 but not Aβ40 or by transient transfection of cDNA encoding Aβ42 sequence. The IκB kinase inhibitor BMS345541 prevents Aβ-induced BACE1 promoter transactivation suggesting that NFκB could mediate this Aβ-associated phenotype. Accordingly, the overexpression of wild-type or Swedish mutated βAPP does not modify the transactivation of BACE1 promoter constructs lacking NFκB-responsive element. Furthermore, APP/β-amyloid precursor protein-like protein deficiency does not affect BACE1 activity and expression. Overall, these data suggest that physiological levels of endogenous Aβ are not sufficient per se to modulate BACE1 promoter transactivation but that exacerbated Aβ production linked to wild-type or Swedish mutated βAPP overexpression modulates BACE1 promoter transactivation and activity via an NFκB-dependent pathway. Alzheimer disease (AD) 3The abbreviations used are:ADAlzheimer diseasePSpresenilinsβAPPβ-amyloid precursor proteinAββ-amyloid peptideAICDAPP intracellular domainAPLP2β-amyloid precursor protein-like protein 2CREBcAMP-response element-binding proteinTricineN-2-hydroxy-1,1-bis(hydroxymethyl)ethylglycineNEPneprilysin. is characterized by abnormal deposition of a set of hydrophobic peptides called amyloid β (Aβ) peptides. The increase of cerebral Aβ levels is one of the common denominators characterizing both sporadic and familial forms of AD and therefore, if not demonstrated as the etiological cause of AD pathology, is often considered as a key factor contributing to the degenerative process (1Hardy J.A. Higgins G.A. Science. 1992; 256: 184-185Crossref PubMed Scopus (5110) Google Scholar). 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Mol. 3: PubMed Google Scholar), we show that cells Aβ cells this production was by DFK167 be that of the DFK167-sensitive production of Aβ in cells expression BACE1 promoter transactivation and in a that was in cells overexpressing and in DFK167 but not increase of BACE1 promoter transactivation and modulation of BACE1 promoter transactivation that Aβ was the for this phenotype. of this exogenous application of Aβ42 but not Aβ40 triggers the transactivation of the BACE1 the transient transfection of constructs harboring the Y. H. Y. N. K. T. H. T. H. K. H. T. M. Checler F. T. T. K. T. J. PubMed Scopus Google also BACE1 promoter whereas for the or for this we that Aβ42 as a of BACE1 transactivation. Aβ could also activities in the of we the of Aβ levels the pathway. We show that expression and activity and by the overexpression of or Aβ-induced of BACE1 of that BACE1 promoter activity was by the factor NFκB C. S. J.R. J. Neurosci. Res. PubMed Scopus Google Scholar). was to the of the NFκB in the Aβ-associated of BACE1. NFκB could be by a of IκB and 2 J.R. M.A. X. J. Y. J. Biol. Chem. 2003; PubMed Scopus Google Scholar), to NFκB we in a the of a of NFκB D. N. A. M. P. G. M. Neurosci. PubMed Scopus Google Scholar), that BMS345541 NFκB activity data not and also the production of both Aβ40 and Aβ42 by cells the of BMS345541 cells not between a effect of the inhibitor NFκB-dependent transactivation of BACE1 promoter and an effect of an of Aβ this we the effect of BMS345541 BACE1 modulation by exogenous application of in in this set of Aβ42 an increased BACE1 promoter transactivation this appears to be by BMS345541 Accordingly, BMS345541 the increase of BACE1 promoter transactivation by overexpression data suggest that BMS345541 triggers effect to Aβ production and that the NFκB the Aβ-induced of BACE1 transactivation. this we the of levels of Aβ to promoter constructs of BACE1, of which of NFκB-responsive the overexpression of or the transactivation of the promoter of BACE1 the of a the NFκB-responsive BACE1 whereas the and not in these cells be that the of was also in the that BMS345541 also BACE1 promoter transactivation in cells and this could that endogenous NFκB in the of BACE1 in phenotype. Overall, data suggest that of BACE1 transactivation of the BACE1 of wild-type and APP and BACE1 promoter transactivation. of the HEK293 cells or cells overexpressing wild-type βAPP or βAPP the BACE1 constructs as and activity was as and to activity as of that observed in cells the BACE1 promoter as and are the of not Aβ BACE1 is that DFK167 not modify BACE1 promoter transactivation in HEK293 cells This that the levels of endogenous Aβ in these cells not be sufficient to alter BACE1 transactivation. this we the of BACE1 expression and activity in fibroblasts. cells not or We show that the of these does not alter BACE1 expression A and or activity Overall, data BACE1 is not by endogenous AICD or Aβ production and that the modulation of BACE1 could be by levels of of the in Alzheimer is the of called A of and that amyloid the of a in AD PubMed Scopus Google Scholar). a key to this is the that if not for and AD in common the to of the the or the of the Aβ peptides generated F. J. Neurochem. 1995; 65: 1431-1444Crossref PubMed Scopus (421) Google Scholar, F. 1999; PubMed Google Scholar). The of the and mechanisms underlying such is of the be that γ-secretase activity could be in Aβ the of an of γ-secretase sporadic AD to be Furthermore, the by also account for for sporadic AD is that modify cleavage alter to the of Aβ modify the of the Aβ the Swedish to the Aβ triggers an of the of Aβ production could be as a common between sporadic and of specific of Aβ could to Aβ and are the putative in Aβ J.A. J. Neurochem. 2002; PubMed Scopus Google Scholar, 2003; PubMed Scopus Google Scholar, E.A. PubMed Scopus Google Scholar). was to Aβ40 Aβ42 K. S. N. Y. K. S. H. H. T. T. J. Biol. Chem. 2001; PubMed Scopus Google Scholar). observed in of familial AD Aβ42 production is could be due to of the Aβ42 Aβ40 the that and decrease in cerebral levels A. S. M.C. Y. PubMed Scopus Google Scholar). This could account for the increase in Aβ levels observed in sporadic of we show that deficiency the activity and promoter transactivation of the β-secretase BACE1. A. K. N. N. T. H. S. R. S. J. Neurosci. Res. PubMed Scopus Google Scholar), we show that of the modulation of BACE1 activity could be for by a in BACE1 of data that γ-secretase activity could also to the of Aβ the overexpression of a catalytically inactive lowers BACE1 the γ-secretase inhibitor DFK167 lowers BACE1 expression and activity in wild-type but not in fibroblasts. The data to which putative product generated by γ-secretase could the of BACE1. We the intracellular of βAPP this product that could account for of BACE1 promoter transactivation. in AICD and are and we to increase in BACE1 activity in wild-type and fibroblasts. AICD was BACE1 was in in transgenic overexpressing both AICD and J. Cell Biol. PubMed Scopus Google Scholar), a R. J. T. C. Alves da Costa C. Vincent B. J. S. P. Checler F. PubMed Scopus Google and C. Alves da and F. to be data by that transient transfection of wild-type βAPP and the N-terminal of βAPP lacking both increase of BACE1 promoter transactivation. of data the that Aβ for the observed effect BACE1. BACE1 activity is by DFK167 in the of HEK293 cells overexpressing wild-type or Swedish mutated βAPP that the that Aβ production also the increase of BACE1 promoter transactivation. exogenous application of Aβ42 but not Aβ40 both promoter transactivation of BACE1. transient transfection of cDNA encoding but not or also increased BACE1 promoter The is of this that the of BACE1 is linked to the of of that physiological of Aβ not BACE1. HEK293 but DFK167-sensitive this inhibitor not modulate BACE1 promoter transactivation in these BACE1 expression and activity in wild-type and which not endogenous levels of The suggest that the of BACE1 by Aβ endogenous of the peptide increase This also that the decrease of BACE1 activity observed in fibroblasts was not of endogenous Aβ but to an product that to be that this effect is of the of this peptide to the of demonstrated that Aβ are the D.M. J. Neurochem. PubMed Scopus Google Scholar). is to that this could the in sporadic of The as to Aβ modulates BACE1 promoter an of BACE1 or if both and mechanisms could We NFκB as a in the of BACE1. the inhibitor of IκB kinase that NFκB activity the increase of BACE1 promoter transactivation. that an NFκB-responsive in the promoter of BACE1 the of and cells to BACE1 promoter transactivation. data a that BACE1 promoter transactivation could be by NFκB in cells C. S. J.R. J. Neurosci. Res. PubMed Scopus Google Scholar). is that the of exogenous Aβ to BACE1 promoter was a but in the of used in a BACE1 promoter activity in and cells C. S. J.R. J. Neurosci. Res. PubMed Scopus Google Scholar). not the Aβ and which and intracellular not be Furthermore, of that the effect by exogenous Aβ42 be as the of Aβ40 BACE1 promoter in transfection to in Y. H. Y. N. K. T. H. T. H. K. H. T. M. Checler F. T. T. K. T. J. PubMed Scopus Google Scholar, but not or the by exogenous the Aβ levels in transfection both exogenous application of Aβ42 and expression of wild-type or APP BACE1 promoter in a be that the of the NFκB-responsive not and increase of BACE1 promoter activity suggesting that mechanisms BACE1 promoter a that appears to as a of BACE1 transactivation this protein expression B. K. J. 2004; PubMed Scopus Google Scholar). is that Aβ to in L. R. J. Biol. Chem. 2001; PubMed Scopus Google Scholar), by the of A. E. A. M. J. Neurochem. Google Scholar). this process appears intracellular Aβ A. E. A. M. J. Neurochem. Google Scholar). Aβ-induced of could to of BACE1, of such modulation of BACE1 by one also that a of Aβ as Y. H. Y. N. K. T. H. T. H. K. H. T. M. Checler F. T. T. K. T. J. PubMed Scopus Google demonstrated that Aβ to of the the Aβ in the promoter the BACE1 this B. D. for for that these Aβ in and promoter constructs transactivation in Overall, Aβ42 as a of BACE1 and that levels of this of Aβ could BACE1 promoter in via the NFκB pathway. This by which production of Aβ42 production could to both sporadic and of Alzheimer We are to B. Strooper and U. for S. for transgenic and T. for Aβ J. F. and J. are for