BACE-1 inhibition prevents the -secretase inhibitor evoked A rise in human neuroblastoma SH-SY5Y cells

Background: accumulation of amyloid -peptide (a) in the plaques is one of the major pathological features in alzheimer's disease (ad). sequential cleavage of amyloid precursor protein (app) by -site app cleaving enzyme 1 (bace-1) and -secretase results in the formation of a peptides. preventing a formation is believed to attenuate ad progression and bace-1 and -secretase are thus attractive targets for ad drug development. methods. combining bace-1 and -secretase inhibition on a secretion from human neuroblastoma sh-sy5y cells was evaluated in this study. secreted a40 and a42 levels were measured from sh-sy5y cells stably transfected with appwt or appswe genes. a selective bace inhibitor and the -secretase inhibitor ly450139 (semagacestat) were used to inhibit respective secretase. results: ly450139 increased a40 and a42 secretion from sh-sy5y appwt cells at low concentrations (by 60% at 3 nm) followed by subsequent inhibition at higher concentrations (ic5090 nm). washout studies showed that the a increase evoked by 3 nm ly450139 was not due to enhanced cleavage following substrate accumulation but rather to activation of a formation. by contrast,ly450139 inhibited a formation from sh-sy5y appswe in a monophasic manner (ic5018 nm). the bace inhibitor per se inhibited a secretion from both sh-sy5y appwt and sh-sy5y appswe cells with ic 50s ranging between 7 - 18 nm and also prevented the increased a secretion evoked by 3 nm ly450139. combining the bace inhibitor with higher inhibitory concentrations of ly450139 failed to demonstrate any clear additive or synergistic effects. conclusion: bace-1 inhibition attenuates the a increase evoked by ly450139 while not providing any obvious synergistic effects on ly450139-mediated inhibition. © 2011 jämsä et al; licensee biomed central ltd.