7-(4-Hydroxy-3-methoxyphenyl)-1-phenyl-4E-hepten-3-one alleviates Abeta1-42 induced cytotoxicity through PI3K-mTOR pathways.
7-(4-Hydroxy-3-methoxyphenyl)-1-phenyl-4E-hepten-3-one alleviates Abeta1-42 induced cytotoxicity through PI3K-mTOR pathways.
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7-(4-羟基-3-甲氧基苯基)-1-苯基-4E-hepten-3-one 通过 PI3K-mTOR 途径减轻 Abeta1-42 诱导的细胞毒性。
DOI：
10.1016/j.bbrc.2017.01.125
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Shi Lei
中科院分区：
文献类型：
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作者：
Xiao Hanlin;Zhang Qinghua;Peng Yinghui;Tang Genyun;Liao Yumei;Zhuang Xiaoji;Ye Wen-Cai;Wang Ying;Shi Lei
阿尔茨海默病（AD）是老年人最常见的神经退行性疾病。越来越多的证据表明，β-淀粉样蛋白（Aβ）的产生是 AD 的关键病理原因。 7-(4-羟基-3-甲氧基苯基)-1-苯基-4E-庚烯-3-酮 (AO-2) 是一种天然二芳基庚烷类化合物，之前被发现具有神经元分化和神经突生长的活性，其类似物显示出针对 Aβ 的保护作用。在这项研究中，我们进一步研究了 AO-2 对 Aβ 诱导的 PC12 细胞和海马神经元损伤的功能。用 AO-2 预处理 PC12 细胞，以浓度依赖性方式恢复细胞活力，对抗 Aβ 诱导的神经毒性。此外，Aβ 刺激的细胞凋亡和 caspase-3 激活被 AO-2 显着抑制。我们发现 AO-2 可以阻止 Aβ 损伤后 PI3K-Akt-mTOR 信号传导的下调，并且阻断 PI3K 或 mTOR 活性会导致 AO-2 对 caspase-3 抑制的失败。我们进一步表明，AO-2 可以防止 Aβ 的两种破坏性影响，即活性氧 (ROS) 产生增加和树突损伤，并且这种保护也依赖于 PI3K 和 mTOR 活性。总而言之，这项研究表明 AO-2 通过 PI3K-mTOR 途径对抗 Aβ 诱导的 PC12 细胞和海马神经元损伤，从而提供一种新的神经保护化合物，可能为 AD 药物开发提供线索。
Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. Increasing evidence has shown that β-amyloid protein (Aβ) production is the key pathological cause of AD. 7-(4-Hydroxy-3-methoxyphenyl)-1-phenyl-4E-hepten-3-one (AO-2), a natural diarylheptanoid, is previously found to have activities in neuronal differentiation and neurite outgrowth, and its analogue shows protective effects against Aβ. In this study, we further investigated the function of AO-2 toward Aβ-induced injuries in PC12 cells and hippocampal neurons. Pretreatment of PC12 cells with AO-2 restored cell viability in a concentration-dependent manner against Aβ-induced neurotoxicity. Moreover, the Aβ stimulated apoptosis and caspase-3 activation were markedly inhibited by AO-2. We found that AO-2 prevented the downregulation of PI3K-Akt-mTOR signaling after Aβ damage, and blockade of either PI3K or mTOR activity led to the failure of AO-2 on caspase-3 inhibition. We further showed that AO-2 was protective against two devastating effects of Aβ, increased reactive oxygen species (ROS) production and dendrite injury, and this protection was also dependent on PI3K and mTOR activities. Taken together, this study showed that AO-2 acts against Aβ-induced damages in PC12 cells and hippocampal neurons through PI3K-mTOR pathways, thus providing a new neuroprotective compound which may shed light on drug development of AD.