Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học Wertheim cung cấp cho các bạn kiến thức về ngành y đề tài: BACE-1 inhibition prevents the g-secretase inhibitor evoked Ab rise in human neuroblastoma SH-SY5Y cells. | Jămsă et al. Journal of Biomedical Science 2011 18 76 http content 18 1 76 tì NSC The cost of publication in Journal of Biomedical Science Is borne by the National Science Council Taiwan JOURNAL OF BIOMEDICAL SCIENCE RESEARCH Open Access BACE-1 inhibition prevents the y-secretase inhibitor evoked Ab rise in human neuroblastoma SH-SY5Y cells Anne Jamsa Oscar Belda Michael Edlund and Erik Lindstrom Abstract Background Accumulation of amyloid b-peptide Ab in the plaques is one of the major pathological features in Alzheimer s disease AD . Sequential cleavage of amyloid precursor protein APP by b-site APP cleaving enzyme 1 BACE-1 and y-secretase results in the formation of Ab peptides. Preventing Ab formation is believed to attenuate AD progression and BACE-1 and g-secretase are thus attractive targets for AD drug development. Methods Combining BACE-1 and y-secretase inhibition on Ab secretion from human neuroblastoma SH-SY5Y cells was evaluated in this study. Secreted Ab40 and Ab42 levels were measured from SH-SY5Y cells stably transfected with APPwt or APPswe genes. A selective BACE inhibitor and the y-secretase inhibitor LY450139 semagacestat were used to inhibit respective secretase. Results LY450139 increased Ab40 and Ab42 secretion from SH-SY5Y APPwt cells at low concentrations by 60 at 3 nM followed by subsequent inhibition at higher concentrations IC50 90 nM . Washout studies showed that the Ab increase evoked by 3 nM LY450139 was not due to enhanced cleavage following substrate accumulation but rather to activation of Ab formation. By contrast LY450139 inhibited Ab formation from SH-SY5Y APPswe in a monophasic manner IC50 18 nM . The BACE inhibitor per se inhibited Ab secretion from both SH-SY5Y APPwt and SH-SY5Y APPswe cells with IC50s ranging between 7 - 18 nM and also prevented the increased Ab secretion evoked by 3 nM LY450139. Combining the BACE inhibitor with higher inhibitory concentrations of LY450139 failed to demonstrate any clear
