糖原合成酶激酶-3β信号通路介导海马CA1区长时程增强的氧化性调节作用
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摘要
第一部分氧化还原剂对海马CA1区长时程增强的调节作用
目的:阿尔茨海默病(Alzheimer disease, AD)是年龄相关性的神经退行性疾病,伴随着进行性的记忆和认知功能障碍。细胞中大量的氧自由基(reactive oxygen species, ROS)所致的氧化性损伤被认为是AD最重要的发病机制之一。目前大量的研究证据表明AD大脑存在氧化性损伤并伴有突触的丧失,特别重要的是Aβ和ROS导致的突触可塑性的功能紊乱是引起早期记忆减退的重要因素。长时程增强(long-term potentiation, LTP)是突触可塑性最重要的一种表现形式,一直以来都被认为是解释记忆和学习的分子和细胞基础的重要模型之一。ROS特别是过氧化氢与LTP的调节有重要的关系,微摩尔浓度的过氧化氢能可逆性的抑制突触传递和可塑性,而毫摩尔的过氧化氢则可以增强LTP。因此,深入研究海马CA1区突触可塑性的氧化调节作用对于进一步理解AD的发病机制和寻找有效的治疗方法具有重要的理论和实际意义。方法:采用细胞外场电位记录的方法研究氧化还原剂对海马CA1区LTP的影响。结果:膜透性的氧化剂氯胺-T(CH-T)可抑制海马CA1区LTP,这种抑制作用可被膜透性的还原剂二硫苏糖醇(DTT)所拮抗,但膜难透性的还原剂TCEP(磷酸三(2-氯乙基)酯)则无此作用。与之不同的是,膜透性的还原剂DTT能够增强海马CA1区LTP,这种增强作用能够被CH-T所逆转,但DTNB(5’-二硫代-2-(2-硝基苯甲酸))对其没有作用。膜难透性的氧化剂DTNB或还原剂TCEP对海马CA1区LTP无作用。在这些氧化还原剂所用的浓度下,这些药物对突触的基础传递和双波易化都没有影响。结论:氧化性调节作用对海马CA1区LTP起重要作用,氧化还原剂对细胞膜通透性难易特性可能是其对LTP作用不同的原因之一。这些结果还提示膜透性的氧化还原剂作用位点可能不在细胞膜表面而是位于细胞内结构或细胞膜深层。
第二部分GSK-3β信号通路参与海马CA1区长时程增强的氧化性调节
目的:糖原合成酶激酶-3β(glycogen synthase kinase-3, GSK-3β)是一种多功能的丝氨酸/苏氨酸蛋白激酶,在氧化应激所致的神经退行性疾病如AD中起着重要的作用;并且GSK-3β参与了海马CA1区突触可塑性的调节。本实验是在第一部分研究氧化还原剂对海马CA1区LTP影响的基础上,进一步阐明GSK-3β这种AD相关的丝氨酸-苏氨酸激酶是否参与这种氧化调节过程。方法:采用细胞外场电位记录和Western Blot的方法研究GSK-3β在氧化还原剂调节海马CA1区LTP中的作用。结果:高频刺激能够引起GSK-3β位点中ser9的磷酸化增加,但总的GSK-3β不变。在CH-T的作用下,高频刺激后GSK-3β中ser9的磷酸化与总的GSK-3β比值和高频刺激组相比降低,与之相反,在DTT作用下,高频刺激后GSK-3β中ser9的磷酸化与总的GSK-3β比值和高频刺激组相比升高。而DTNB或TCEP对高频刺激后GSK-3β中ser9的磷酸化与总的GSK-3β比值无明显影响。为进一步研究GSK-3β的失活是否参与氧化还原剂对LTP的调节,采用电生理记录的方法研究GSK-3β抑制剂氯化锂(LiCl)对氧化还原剂调节LTP的影响。LiCl能够完全逆转CH-T对LTP的抑制作用,而预先孵育LiCl能够增加LTP的强度,与单独给予DTT的结果很相似。进一步分析发现预先孵育LiCl后再给予DTT所导致LTP的增加与单独给予LiCl后LTP的增加间无明显差异。采用Western Blot的方法研究单独给予LiCl或同时给予LiCl和氧化还原剂时GSK-3β活性的变化。结果发现LiCl可逆转CH-T所致的GSK-3β磷酸化减少;LiCl和DTT都能够增加GSK-3β磷酸化的水平,两组之间无明显差异;也发现同时给予LiCl和DTT与单独给予LiCl相比,GSK-3β磷酸化的水平无明显差异。结论:GSK-3β参与氧化还原剂对海马CA1区LTP的调节作用,本研究结果为进一步了解氧化调节在AD记忆损伤发病机制中的作用提供新的依据和治疗靶点。
PartⅠRedox modulation of long-term potentiation in the hippocampus
Background:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, characterized by a progressive loss of memory and cognitive functions. There is now considerable evidence that impaired redox regulation is implicated in AD with a synaptic failure, and in particular, that amyloid beta (Aβ) and ROS induced dysfunction of synaptic plasticity contributes to early memory loss that precedes neuronal degeneration. A prominent form of synaptic plasticity known as long-term potentiation (LTP) has consolidated its status as the preeminent synaptic model for investigating the molecular and cellular basis of learning and memory. ROS particularly hydrogen peroxide (H2O2) and modulation of LTP has been proposed. Millimolar concentrations of H2O2 irreversibly suppress synaptic transmission and plasticity, whereas micromolar concentrations enhance LTP. Methods:Field potentials were evoked by a constant stimulation in the Schaffer collaterals with a bipolar electrode and recorded in the stratum radiatum layer of CA1 with a glass micropipette. Results:In the present study, we find that membrane-permeable oxidizing agent CH-T inhibits the induction of LTP in CA1 region of hippocampus in vitro, which can be restored by pretreatment with DTT but not by TCEP. In contrast, membrane-permeable reducing agent DTT enhanced the induction of LTP in CA1 region of hippocampus, which can be reversed by pretreatment with CH-T but not by DTNB. However, neither membrane-impermeable oxidizing agent DTNB nor membrane-impermeable reducing agent TCEP can affect the induction of LTP. The concentrations of redox agents used did not affect the basic synaptic transmission and PPF. Conclusion:The characteristics of their membrane-permeable or membrane-impermeable ability may contribute to explain their different effects on LTP. These results also demonstrated that the targets of redox regulation are not on the surface of cell membrane, but located in the intracellular structures or internal surface of cell membrane.
PartⅡRedox modulation of long-term potentiation in the hippocampus via regulation of GSK-3βpathway
Background:GSK-3βis well known to play critical roles in oxidative stress-induced neurodegenerative disease such as AD. Recent study shows that phosphorylation at the inhibitory Ser9 site on GSK-3βis increased upon induction of LTP in both hippocampal CA1 and dentate gyrus (DG). In order to explore a role for GSK-3βin redox modulation of LTP, we investigated the phosphorylation status of GSK-3βin CA1 area of hippocampal slices after HFS. Methods:Field potentials recordings and Western Blot were used to evaluate the effects of GSK-3β. Results:HFS induction caused an increase in the phosphorylation of GSK-3βser9, but with no change in total GSK-3β. Treatment with CH-T decreased the ratio of pGSK-3βto total GSK-3β. In contrast, the ratio of pGSK-3βto total GSK-3βwas increased markedly in DTT-treated slices. No significant changes were found in relative ratio of pGSK-3βto total GSK-3βin DTNB or TCEP-treated slices. To directly examine the possibility that GSK-3βinactivity may be required for the redox modulation of LTP, we then determined the effects of LiCl, an inhibitor of GSK-3β, on LTP modulation by CH-T. LiCl (10 mM) completely blocked the inhibitory effects of CH-T on LTP. There were no significant differences of LTP magnitudes between control group and LiCl combined CH-T group. Next, we sought to determine whether LiCl mimicked the effects of DTT on the induction of LTP. We found that preincubation of LiCl increased the magnitudes of LTP similar to that of DTT alone. Furthermore, after incubation of LiCl, application of DTT produced a significant increase in LTP magnitude, which was similar to that of LiCl alone. We then measured the phosphorylation of GSK-3β in presence of LiCl alone or LiCl plus redox agents. Preincubation with LiCl before CH-T reversed the decrease ratio of pGSK-3βto total GSK-3βas found in CH-T group. There was no difference in the ratio of pGSK-3βto total GSK-3βbetween LiCl group and DTT group. Preincubation of LiCl increased the ratio of pGSK-3βto total GSK-3βsimilar to that of LiCl plus DTT group. Conclusion:The effects of these membrane-permeable redox agents are at least partially attributed to the modification of GSK-3β. These findings are benefit for understanding of redox contribution to mechanisms underlying AD pathogenesis and its promising therapeutic target.
目的:阿尔茨海默病(Alzheimer disease, AD)是年龄相关性的神经退行性疾病,伴随着进行性的记忆和认知功能障碍。细胞中大量的氧自由基(reactive oxygen species, ROS)所致的氧化性损伤被认为是AD最重要的发病机制之一。目前大量的研究证据表明AD大脑存在氧化性损伤并伴有突触的丧失,特别重要的是Aβ和ROS导致的突触可塑性的功能紊乱是引起早期记忆减退的重要因素。长时程增强(long-term potentiation, LTP)是突触可塑性最重要的一种表现形式,一直以来都被认为是解释记忆和学习的分子和细胞基础的重要模型之一。ROS特别是过氧化氢与LTP的调节有重要的关系,微摩尔浓度的过氧化氢能可逆性的抑制突触传递和可塑性,而毫摩尔的过氧化氢则可以增强LTP。因此,深入研究海马CA1区突触可塑性的氧化调节作用对于进一步理解AD的发病机制和寻找有效的治疗方法具有重要的理论和实际意义。方法:采用细胞外场电位记录的方法研究氧化还原剂对海马CA1区LTP的影响。结果:膜透性的氧化剂氯胺-T(CH-T)可抑制海马CA1区LTP,这种抑制作用可被膜透性的还原剂二硫苏糖醇(DTT)所拮抗,但膜难透性的还原剂TCEP(磷酸三(2-氯乙基)酯)则无此作用。与之不同的是,膜透性的还原剂DTT能够增强海马CA1区LTP,这种增强作用能够被CH-T所逆转,但DTNB(5’-二硫代-2-(2-硝基苯甲酸))对其没有作用。膜难透性的氧化剂DTNB或还原剂TCEP对海马CA1区LTP无作用。在这些氧化还原剂所用的浓度下,这些药物对突触的基础传递和双波易化都没有影响。结论:氧化性调节作用对海马CA1区LTP起重要作用,氧化还原剂对细胞膜通透性难易特性可能是其对LTP作用不同的原因之一。这些结果还提示膜透性的氧化还原剂作用位点可能不在细胞膜表面而是位于细胞内结构或细胞膜深层。
第二部分GSK-3β信号通路参与海马CA1区长时程增强的氧化性调节
目的:糖原合成酶激酶-3β(glycogen synthase kinase-3, GSK-3β)是一种多功能的丝氨酸/苏氨酸蛋白激酶,在氧化应激所致的神经退行性疾病如AD中起着重要的作用;并且GSK-3β参与了海马CA1区突触可塑性的调节。本实验是在第一部分研究氧化还原剂对海马CA1区LTP影响的基础上,进一步阐明GSK-3β这种AD相关的丝氨酸-苏氨酸激酶是否参与这种氧化调节过程。方法:采用细胞外场电位记录和Western Blot的方法研究GSK-3β在氧化还原剂调节海马CA1区LTP中的作用。结果:高频刺激能够引起GSK-3β位点中ser9的磷酸化增加,但总的GSK-3β不变。在CH-T的作用下,高频刺激后GSK-3β中ser9的磷酸化与总的GSK-3β比值和高频刺激组相比降低,与之相反,在DTT作用下,高频刺激后GSK-3β中ser9的磷酸化与总的GSK-3β比值和高频刺激组相比升高。而DTNB或TCEP对高频刺激后GSK-3β中ser9的磷酸化与总的GSK-3β比值无明显影响。为进一步研究GSK-3β的失活是否参与氧化还原剂对LTP的调节,采用电生理记录的方法研究GSK-3β抑制剂氯化锂(LiCl)对氧化还原剂调节LTP的影响。LiCl能够完全逆转CH-T对LTP的抑制作用,而预先孵育LiCl能够增加LTP的强度,与单独给予DTT的结果很相似。进一步分析发现预先孵育LiCl后再给予DTT所导致LTP的增加与单独给予LiCl后LTP的增加间无明显差异。采用Western Blot的方法研究单独给予LiCl或同时给予LiCl和氧化还原剂时GSK-3β活性的变化。结果发现LiCl可逆转CH-T所致的GSK-3β磷酸化减少;LiCl和DTT都能够增加GSK-3β磷酸化的水平,两组之间无明显差异;也发现同时给予LiCl和DTT与单独给予LiCl相比,GSK-3β磷酸化的水平无明显差异。结论:GSK-3β参与氧化还原剂对海马CA1区LTP的调节作用,本研究结果为进一步了解氧化调节在AD记忆损伤发病机制中的作用提供新的依据和治疗靶点。
PartⅠRedox modulation of long-term potentiation in the hippocampus
Background:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, characterized by a progressive loss of memory and cognitive functions. There is now considerable evidence that impaired redox regulation is implicated in AD with a synaptic failure, and in particular, that amyloid beta (Aβ) and ROS induced dysfunction of synaptic plasticity contributes to early memory loss that precedes neuronal degeneration. A prominent form of synaptic plasticity known as long-term potentiation (LTP) has consolidated its status as the preeminent synaptic model for investigating the molecular and cellular basis of learning and memory. ROS particularly hydrogen peroxide (H2O2) and modulation of LTP has been proposed. Millimolar concentrations of H2O2 irreversibly suppress synaptic transmission and plasticity, whereas micromolar concentrations enhance LTP. Methods:Field potentials were evoked by a constant stimulation in the Schaffer collaterals with a bipolar electrode and recorded in the stratum radiatum layer of CA1 with a glass micropipette. Results:In the present study, we find that membrane-permeable oxidizing agent CH-T inhibits the induction of LTP in CA1 region of hippocampus in vitro, which can be restored by pretreatment with DTT but not by TCEP. In contrast, membrane-permeable reducing agent DTT enhanced the induction of LTP in CA1 region of hippocampus, which can be reversed by pretreatment with CH-T but not by DTNB. However, neither membrane-impermeable oxidizing agent DTNB nor membrane-impermeable reducing agent TCEP can affect the induction of LTP. The concentrations of redox agents used did not affect the basic synaptic transmission and PPF. Conclusion:The characteristics of their membrane-permeable or membrane-impermeable ability may contribute to explain their different effects on LTP. These results also demonstrated that the targets of redox regulation are not on the surface of cell membrane, but located in the intracellular structures or internal surface of cell membrane.
PartⅡRedox modulation of long-term potentiation in the hippocampus via regulation of GSK-3βpathway
Background:GSK-3βis well known to play critical roles in oxidative stress-induced neurodegenerative disease such as AD. Recent study shows that phosphorylation at the inhibitory Ser9 site on GSK-3βis increased upon induction of LTP in both hippocampal CA1 and dentate gyrus (DG). In order to explore a role for GSK-3βin redox modulation of LTP, we investigated the phosphorylation status of GSK-3βin CA1 area of hippocampal slices after HFS. Methods:Field potentials recordings and Western Blot were used to evaluate the effects of GSK-3β. Results:HFS induction caused an increase in the phosphorylation of GSK-3βser9, but with no change in total GSK-3β. Treatment with CH-T decreased the ratio of pGSK-3βto total GSK-3β. In contrast, the ratio of pGSK-3βto total GSK-3βwas increased markedly in DTT-treated slices. No significant changes were found in relative ratio of pGSK-3βto total GSK-3βin DTNB or TCEP-treated slices. To directly examine the possibility that GSK-3βinactivity may be required for the redox modulation of LTP, we then determined the effects of LiCl, an inhibitor of GSK-3β, on LTP modulation by CH-T. LiCl (10 mM) completely blocked the inhibitory effects of CH-T on LTP. There were no significant differences of LTP magnitudes between control group and LiCl combined CH-T group. Next, we sought to determine whether LiCl mimicked the effects of DTT on the induction of LTP. We found that preincubation of LiCl increased the magnitudes of LTP similar to that of DTT alone. Furthermore, after incubation of LiCl, application of DTT produced a significant increase in LTP magnitude, which was similar to that of LiCl alone. We then measured the phosphorylation of GSK-3β in presence of LiCl alone or LiCl plus redox agents. Preincubation with LiCl before CH-T reversed the decrease ratio of pGSK-3βto total GSK-3βas found in CH-T group. There was no difference in the ratio of pGSK-3βto total GSK-3βbetween LiCl group and DTT group. Preincubation of LiCl increased the ratio of pGSK-3βto total GSK-3βsimilar to that of LiCl plus DTT group. Conclusion:The effects of these membrane-permeable redox agents are at least partially attributed to the modification of GSK-3β. These findings are benefit for understanding of redox contribution to mechanisms underlying AD pathogenesis and its promising therapeutic target.
引文
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