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

ABSTRACT: 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 A?40 and A?42 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 A?40 and A?42 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 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 (IC(50) 18 nM). The BACE inhibitor per se inhibited A? 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 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.

SUBMITTER: Jamsa A

PROVIDER: S-EPMC3217850 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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

Jämsä Anne A Belda Oscar O Edlund Michael M Lindström Erik E

Journal of biomedical science 20111021

<h4>Background</h4>Accumulation of amyloid β-peptide (Aβ) in the plaques is one of the major pathological features in Alzheimer's disease (AD). Sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE-1) and γ-secretase results in the formation of Aβ peptides. Preventing Aβ formation is believed to attenuate AD progression and BACE-1 and γ-secretase are thus attractive targets for AD drug development.<h4>Methods</h4>Combining BACE-1 and γ-secretase inhibition ...[more]

PMID: 22018341

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Project description:BackgroundMaleic acid is a multi-functional chemical widely used in the field of industrial chemistry for producing food additives and food contact materials. As maleic acid may contaminate food by the release from food packages or intentional addition, it raises the concern about the effects of excessive dietary exposure to maleic acid on human health. However, the influence of maleic acid on human health has not been thoroughly studied. In silico toxicogenomics approaches have found the association between maleic acid and nervous system disease in human. The aim of this study is to experimentally explore the effects of maleic acid on human neuronal cells.MethodsA microarray-based transcriptome profiling was performed to offer a better understanding of the effects of maleic acid on human health. Gene expression profiles of human neuroblastoma SH-SY5Y cells exposed to three concentrations of maleic acid (10, 50, and 100 μM) for 24 h were analyzed. Genes which were differentially expressed in dose-dependent manners were identified and further analyzed with an enrichment analysis. The expression profile of selected genes related to the inferred functional changes was validated using quantitative polymerase chain reaction (qPCR). Specific fluorescence probes were applied to observe the inferred functional changes in maleic acid-treated neuronal cells.ResultsA total of 316 differentially expressed genes (141 upregulated and 175 downregulated) were identified in response to the treatment of maleic acid. The enrichment analysis showed that DNA binding and metal ion binding were the significant molecular functions (MFs) of the neuronal cells affected by maleic acid. Maleic acid exposure decreased the expression of genes associated with calcium and thiol levels of the cells in a dose-dependent manner. The levels of intracellular calcium and thiol levels were also affected by maleic acid dose-dependent.DiscussionThe exposure to maleic acid is found to decrease the cellular calcium and thiol levels in human neuronal cells at both transcriptional and functional levels. This study reported the first transcriptomic profiling of human neuronal cells treated with maleic acid. It is also the first experimental validation of chemical effects predicted by in silico toxicogenomics approaches. The proposed approach may be useful in understanding the potential effects of other poorly characterized chemicals on human health.

Dataset Information

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

Publications

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

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