Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract.
Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract.
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DOI：
10.1016/j.jnutbio.2009.08.005
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发表时间：
2010-10
影响因子：
5.6
通讯作者：
Joseph, James A.
中科院分区：
文献类型：
--
作者：
Brewer, Gregory J.;Torricelli, John R.;Lindsey, Amanda L.;Kunz, Elizabeth Z.;Neuman, A.;Fisher, Derek R.;Joseph, James A.
需要进一步澄清，以解决悖论，记忆的形成，衰老和神经退行性病变都涉及钙内流，氧自由基的产生（ROS）和某些信号通路的激活。在老年大鼠和APP/PS-1小鼠中，认知和海马Ca 2+失调通过补充高抗氧化蓝莓提取物的食物来逆转。在这里，我们研究了神经元是否是蓝莓提取物的重要靶点，以及该机制是否涉及通过MAPK和CREB改变ROS信号传导，这些通路已知在响应淀粉样蛋白β时被激活。原代海马神经元的分离和培养从胚胎，中年或老年（24个月）大鼠。蓝莓提取物被发现在所有年龄段对淀粉样蛋白β神经毒性具有同样的神经保护作用。随着年龄的增长，β淀粉样蛋白毒性的增加与神经元对pERK的免疫反应性的年龄相关性增加和pCREB的年龄无关性增加有关。蓝莓提取物治疗强烈抑制这些增加与神经保护平行。同时标记的ROS和谷胱甘肽与二氯荧光素和monocholorobimane蓝莓提取物的作用机制，涉及短暂的ROS生成的氧化还原缓冲液，谷胱甘肽的增加。我们得出结论，老年神经元对淀粉样蛋白β毒性的年龄相关易感性增加可能是由于pERK和pCREB通路的激活水平较高，蓝莓提取物可以通过ROS应激反应抑制这两种通路来保护这些通路。这些结果表明，蓝莓提取物的有益作用可能涉及瞬时应激信号传导和ROS保护，这可能转化为给予蓝莓提取物的衰老大鼠和APP/PS1小鼠的认知改善。
Further clarification is needed to address the paradox that memory formation, aging and neurodegeneration all involve calcium influx, oxyradical production (ROS) and activation of certain signaling pathways. In aged rats and in APP/PS-1 mice, cognitive and hippocampal Ca2+ dysregulation were reversed by food supplementation with a high antioxidant blueberry extract. Here, we studied whether neurons were an important target of blueberry extract and whether the mechanism involved altered ROS signaling through MAPK and CREB, pathways known to be activated in response to amyloid-beta. Primary hippocampal neurons were isolated and cultured from embryonic, middle-age or old-age (24 months) rats. Blueberry extract was found to be equally neuroprotective against amyloid-beta neurotoxicity at all ages. Increases in amyloid-beta toxicity with age were associated with age-related increases in immunoreactivity of neurons to pERK and an age-independent increase in pCREB. Treatment with blueberry extract strongly inhibited these increases in parallel with neuroprotection. Simultaneous labeling for ROS and for glutathione with dichlorofluorescein and monocholorobimane showed a mechanism of action of blueberry extract to involve transient ROS generation with an increase in the redox buffer, glutathione. We conclude that the increased age-related susceptibility of old-age neurons to amyloid-beta toxicity may be due to higher levels of activation of pERK and pCREB pathways that can be protected by blueberry extract through inhibition of both these pathways through an ROS stress response. These results suggest that the beneficial effects of blueberry extract may involve transient stress signaling and ROS protection that may translate into improved cognition in aging rats and APP/PS1 mice given blueberry extract.
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