Inhibition of γ-secretase decreases β-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA and protein levels, and its protease activity. (a–c) In SK-N-BE cells, inhibition of γ-secretase with the transition analogue L685,458 prevented the increase of BACE1 mRNA level (a), protein level (b) and enzyme activity (c) of BACE1, that are induced by 4-hydroxynonenal (HNE) and H2O2 in control cells. Addition of BACE1 inhibitor IV halved the basal activity of BACE1 and completely blocked its significant increase induced by oxidative stress (OS) (c). (d) In SK-N-BE cells, simultaneous knock-down of PS1/2 by RNA interference reduced the basal level of BACE1 protein levels and prevented the increase of BACE1 by HNE and H2O2. Non-silencing shRNA-treated cells exhibited BACE1 levels similar to those of wild-type cells. Experiments were performed in triplicate; *p < 0.05.