Department of Pathology, Chongqing Medical University, Yuzhong District Yuanjiagang No. 1, 400016, Chongqing, China.
Pharmacol Rep. 2011;63(5):1101-8. doi: 10.1016/s1734-1140(11)70629-6.
Curcumin has been reported to inhibit the generation of Aβ, but the underlying mechanisms by which this occurs remain unknown. Aβ is thought to play an important role in the pathogenesis of Alzheimer's disease (AD). The amyloid hypothesis argues that aggregates of Aβ trigger a complex pathological cascade that leads to neurodegeneration. Aβ is generated by the processing of APP (amyloid precursor protein) by β- and γ-secretases. Presenilin 1 (PS1) is central to γ-secretase activity and is a substrate for GSK-3β, both of which are implicated in the pathogenesis of AD. The present study aimed to investigate the effects of curcumin on the generation of Aβ in cultured neuroblastoma cells and on the in vitro expression of PS1 and GSK-3β. To stimulate Aβ production, a plasmid expressing APP was transfected into human SH-SY5Y neuroblastoma cells. The transfected cells were then treated with curcumin at 0-20 μM for 24 h or with 5 μM curcumin for 0-48 h, and the extracellular levels of Aβ(40/42) were determined by ELISA. The levels of PS1 and GSK-3β mRNA were measured by RT-PCR, and the expression of the PS1 and GSK-3β proteins (including the phosphorylated form of GSK-3β, p-GSK-3β-Ser9) were evaluated by western blotting. Curcumin treatment was found to markedly reduce the production of Aβ(40/42). Treatment with curcumin also decreased both PS1 and GSK-3β mRNA and protein levels in a dose- and time-dependent manner. Furthermore, curcumin increased the inhibitory phosphorylation of GSK-3β protein at Ser9. Therefore, we propose that curcumin decreases Aβ production by inhibiting GSK-3β-mediated PS1 activation.
姜黄素已被报道可抑制 Aβ 的产生，但具体的作用机制尚不清楚。Aβ 被认为在阿尔茨海默病（AD）的发病机制中起重要作用。淀粉样蛋白假说认为，Aβ 的聚集触发了导致神经退行性变的复杂病理级联反应。Aβ 是由 APP（淀粉样前体蛋白）被β-和γ-分泌酶切割产生的。早老素 1（PS1）是 γ-分泌酶活性的核心，也是 GSK-3β 的底物，这两者都与 AD 的发病机制有关。本研究旨在探讨姜黄素对培养的神经母细胞瘤细胞中 Aβ 的产生以及 PS1 和 GSK-3β 的体外表达的影响。为了刺激 Aβ 的产生，将表达 APP 的质粒转染入人 SH-SY5Y 神经母细胞瘤细胞中。然后将转染的细胞用 0-20μM 的姜黄素处理 24 小时或用 5μM 的姜黄素处理 0-48 小时，通过 ELISA 测定细胞外 Aβ（40/42）的水平。通过 RT-PCR 测定 PS1 和 GSK-3βmRNA 的水平，并通过 Western blot 评估 PS1 和 GSK-3β 蛋白（包括 GSK-3β 的磷酸化形式，p-GSK-3β-Ser9）的表达。结果发现，姜黄素处理可显著减少 Aβ（40/42）的产生。姜黄素处理还呈剂量和时间依赖性地降低 PS1 和 GSK-3β mRNA 和蛋白水平。此外，姜黄素增加了 GSK-3β 蛋白 Ser9 位点的抑制性磷酸化。因此，我们提出姜黄素通过抑制 GSK-3β 介导的 PS1 激活来减少 Aβ 的产生。
