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J. Biol. Chem., Vol. 283, Issue 15, 10037-10047, April 11, 2008

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NFB-dependent Control of BACE1 Promoter Transactivation by Aβ42^*

Virginie Buggia-Prevot¹, Jean Sevalle, Steffen Rossner, and Frédéric Checler²

From the Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097 CNRS/UNSA, Equipe Labellisée Fondation pour la Recherche Médicale, 06560 Valbonne, France and the Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany

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 -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 -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 -secretase. The overexpression of APP intracellular domain (AICD), the /-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 APP (the N-terminal product of βAPP generated by -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 IB kinase inhibitor BMS345541 prevents Aβ-induced BACE1 promoter transactivation suggesting that NFB 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 NFB-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 NFB-dependent pathway.

Received for publication, August 8, 2007 , and in revised form, January 24, 2008.

^* This work was supported in part by the CNRS, by European Union Contract LSHM-CT-2003-503330 (Abnormal Proteins in the Pathogenesis of Neuro-degenerative Disorders), by the Fondation pour la Recherche Médicale, and by Unis pour la Recherche sur la Maladie d'Alzheimer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Fondation pour la Recherche Médicale.

² To whom correspondence should be addressed. Tel.: 33-4-93-95-77-60; Fax: 33-4-93-95-77-08; E-mail: checler{at}ipmc.cnrs.fr.

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