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摘要
beta-Amyloid (A beta) peptides that accumulate in Alzheimer disease are generated from the beta-amyloid precursor protein (beta APP) by cleavages by beta-secretase BACE1 and by presenilin-dependent beta-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 beta-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 beta-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 APP epsilon (the N-terminal product of beta APP generated by epsilon-secretase cleavage harboring the A domain but lacking the AICD sequence), suggesting that the production of A beta could account for the modulation of BACE1. Accordingly, we show that HEK293 cells overexpressing wild-type beta APP exhibit a DFK167-sensitive increase in BACE1 promoter transactivation that is increased by the A beta-potentiating Swedish mutation. This effect was mimicked by exogenous application of A beta 42 but not A beta 40 or by transient transfection of cDNA encoding A beta 42 sequence. The I kappa B kinase inhibitor BMS345541 prevents A beta-induced BACE1 promoter transactivation suggesting that NF kappa B could mediate this A beta-associated phenotype. Accordingly, the overexpression of wild-type or Swedish mutated beta APP does not modify the transactivation of BACE1 promoter constructs lacking NF kappa B-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 A beta are not sufficient per se to modulate BACE1 promoter transactivation but that exacerbated A beta production linked to wild-type or Swedish mutated beta APP overexpression modulates BACE1 promoter transactivation and activity via an NF kappa B-dependent pathway.
- 出版日期2008-4-11
