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BACE-1 Inhibition Prevents the γ-secretase Inhibitor Evoked Aβ Rise in Human Neuroblastoma SH-SY5Y Cells

BACE-1 Inhibition Prevents the γ-secretase Inhibitor Evoked Aβ Rise in Human Neuroblastoma SH-SY5Y Cells

Anne Jämsä, Oscar Belda, Michael Edlund, Erik Lindström

J Biomed Sci. 2011 Oct 21;18(1):76.

PMID: 22018341

Abstract:

Background:
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.
Methods:
Combining BACE-1 and γ-secretase inhibition on Aβ secretion from human neuroblastoma SH-SY5Y cells was evaluated in this study. Secreted Aβ40 and Aβ42 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 Aβ40 and Aβ42 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 Aβ increase evoked by 3 nM LY450139 was not due to enhanced cleavage following substrate accumulation but rather to activation of Aβ formation. By contrast, LY450139 inhibited Aβ formation from SH-SY5Y APPswe in a monophasic manner (IC(50) 18 nM). The BACE inhibitor per se inhibited Aβ 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 Aβ 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 Aβ increase evoked by LY450139 while not providing any obvious synergistic effects on LY450139-mediated inhibition.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP425386603	LY450139		425386-60-3	Price

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