BACE-1 inhibition prevents the γ-secretase inhibitor evoked Aß rise in human neuroblastoma SH-SY5Y cells.
J Biomed Sci
; 18: 76, 2011 Oct 21.
Article
em En
| MEDLINE
| ID: mdl-22018341
ABSTRACT
BACKGROUND:
Accumulation of amyloid ß-peptide (Aß) in the plaques is one of the major pathological features in Alzheimer's disease (AD). Sequential cleavage of amyloid precursor protein (APP) by ß-site APP cleaving enzyme 1 (BACE-1) and γ-secretase results in the formation of Aß peptides. Preventing Aß formation is believed to attenuate AD progression and BACE-1 and γ-secretase are thus attractive targets for AD drug development.METHODS:
Combining BACE-1 and γ-secretase inhibition on Aß secretion from human neuroblastoma SH-SY5Y cells was evaluated in this study. Secreted Aß40 and Aß42 levels were measured from SH-SY5Y cells stably transfected with APPwt or APPswe genes. A selective BACE inhibitor and the γ-secretase inhibitor LY450139 (semagacestat) were used to inhibit respective secretase.RESULTS:
LY450139 increased Aß40 and Aß42 secretion from SH-SY5Y APPwt cells at low concentrations (by 60% at 3 nM) followed by subsequent inhibition at higher concentrations (IC(50) 90 nM). Washout studies showed that the Aß increase evoked by 3 nM LY450139 was not due to enhanced cleavage following substrate accumulation but rather to activation of Aß formation. By contrast, LY450139 inhibited Aß formation from SH-SY5Y APPswe in a monophasic manner (IC(50) 18 nM). The BACE inhibitor per se inhibited Aß secretion from both SH-SY5Y APPwt and SH-SY5Y APPswe cells with IC(50)s ranging between 7 - 18 nM and also prevented the increased Aß 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 Aß increase evoked by LY450139 while not providing any obvious synergistic effects on LY450139-mediated inhibition.
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Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Ácido Aspártico Endopeptidases
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Secretases da Proteína Precursora do Amiloide
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Doença de Alzheimer
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article