Formononetin Protects Neurons Against Hypoxia-Induced Cytotoxicity Through Upregulation of ADAM10 and sAβPPα
Formononetin Protects Neurons Against Hypoxia-Induced Cytotoxicity Through Upregulation of ADAM10 and sAβPPα
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Formononetin 通过上调 ADAM10 和 sAβPPα 保护神经元免受缺氧诱导的细胞毒性。
DOI：
10.3233/jad-2011-110506
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Chui, Dehua
中科院分区：
文献类型：
--
作者：
Sun, Miao;Zhou, Ting;Chui, Dehua
刺芒柄花素是中药黄芪的一种活性成分，据报道对阿尔茨海默病（AD）有有益作用。然而，这种效应的机制仍有待阐明。本研究表明，刺芒柄花素增加可溶性a β ppα (sAβPPα)的分泌，从而保护人a β pp瑞典突变细胞（N2a-AβPP细胞）免于缺氧诱导的凋亡。我们以缺氧n2a - a- β pp细胞作为ad样病理的体外模型，证实了定期给予刺芒柄花素治疗具有神经保护作用，随后分别降低了caspase 3活性和提高了细胞活力。引人注目的是，我们的数据显示，刺芒柄花素的caspase 3阻断作用主要是通过刺激α-分泌酶切割AβPP，增加其可溶性形式sAβPPα的分泌来介导的。此外，α-分泌酶复合物抑制剂TAPI-2完全抑制了芒柄花素的保护作用，提示sAβPPα通路在芒柄花素的神经保护反应中起作用。我们还发现芒柄花素对α-分泌酶活性的促进作用主要是通过在转录水平上调ADAM10的表达来实现的。总之，我们的研究为芒柄花素如何介导adam10 - sa - β ppα通路的刺激并发挥神经元保护作用提供了新的见解。
Formononetin, an active constituent of the Chinese herb Astragali Radix, has been reported to have beneficial effects for Alzheimer's disease (AD). Yet the mechanism of this effect remains to be elucidated. The present study shows that formononetin increases soluble-AβPPα (sAβPPα) secretion and thus protects human-AβPP Swedish mutation cell (N2a-AβPP cell) from hypoxia-induced apoptosis. Using hypoxic N2a-AβPP cell as an in vitro model of AD-like pathology, we confirmed that regular treatment with formononetin could have neuroprotective effects, followed respectively by reduced caspase 3 activity and increased cell viability. Strikingly, our data revealed that the caspase 3-blocking effect of formononetin was largely mediated by stimulation of α-secretase cleavage of AβPP, and increasing the secretion of its soluble form, sAβPPα. Moreover, the protective effect of formononetin was totally inhibited by TAPI-2, an α-secretase complex inhibitor, suggesting the role of the sAβPPα pathway in the neuroprotective response to formononetin. We also found that the stimulative effect of formononetin on α-secretase activity was mainly conducted by upregulating ADAM10 expression at the transcriptional level. Altogether, our study provides novel insights into how formononetin mediates stimulation of the ADAM10-sAβPPα pathway and exerts a neuronal protective effect.