- 作者: Anne Jamsa, Oscar Belda, Michael Edlund and Erik Lindstrom
- 作者服務機構: PO Box 1086, S-14122 Huddinge, Sweden
- 中文摘要: --
- 英文摘要:
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 (IC50 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 (IC50 18
nM). The BACE inhibitor per se inhibited Aβ secretion from both SH-SY5Y APPwt
and SH-SY5Y APPswe cells with IC50s 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. - 中文關鍵字: --
- 英文關鍵字: --