糖原合酶激酶-3促进成年大鼠海马的神经发生及其机制的探讨
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摘要
神经发生在成年哺乳动物脑内仍然持续存在,并主要局限于海马齿状回的亚颗粒层( Subgranular zone, SGZ)和前脑的室管膜下区(Subventricular zone, SVZ)两个脑区。阿尔兹海默病(Alzheimer’s disease, AD)是老年人常见的一种慢性进行性神经退行性疾病,其患者脑内海马区神经发生的水平明显高于正常人,目前对此现象产生的机制仍不清楚。目前针对AD尚无有效的治疗措施,刺激患者脑内新生神经元的产生增多使其替代衰老、死亡的神经元发挥正常功能成为目前极具前景的一个治疗靶点。因此,了解AD患者脑内影响神经发生的相关因素,弄清其脑内神经发生水平增高的原因具有重要的意义。
以过度磷酸化的微管相关蛋白tau为主要成分的神经原纤维缠结(neurofibrillary tangles, NFTs)是AD患者脑内主要的病理特征之一,糖原合酶激酶-3β(glycogen synthase kinase 3, GSK-3β)是导致tau蛋白过度磷酸化的关键激酶,与AD病变的发展具有密切的联系。此外,tau蛋白与GSK-3β在神经元的发育中也具有重要作用。本研究旨在通过观察GSK-3β活性增高对成年大鼠脑内神经发生的影响及磷酸化tau蛋白在SGZ区和SVZ区与新生神经元之间的关系,探讨AD患者脑内神经发生水平增高的可能机制。
为探讨GSK-3β与成年神经发生的关系,我们首先采用免疫荧光双标的技术对成年大鼠脑内SGZ区和SVZ区GSK-3β与未成熟神经元之间的关系进行了观察;接下来,为观察GSK-3β活性增高对成年神经发生的影响,我们将动物分为2组,通过侧脑室定位注射生理盐水(NS组)或PI3K特异性抑制剂wortmannin(WT组),并分别于术后不同时间点取材,采用免疫组化的方法对大鼠脑内神经发生的水平进行测定;为进一步明确GSK-3β对成年神经发生的作用,我们将动物分为5组,通过侧脑室注射分别给予10μl的NS、10μMWT、100μMWT、70μM的GSK-3β特异性抑制剂SB216763 ( SB )或100μMWT和70μM SB联合给药,术后3天取材,采用免疫印迹的方法对大鼠脑内神经发生的水平进行测定;为探讨GSK-3β活性增高对成年大鼠齿状回内细胞增殖、分化及存活的影响,我们在侧脑室给药前对大鼠进行连续3天的BrdU腹腔注射,标记此时处于增殖期的新生细胞,并于术后跟踪观察BrdU+细胞的数量改变及分化情况。
结果显示:
1. GSK-3β广泛分布于成年大鼠海马齿状回及前脑的室管膜下区,与新生神经元存在明显的共定位关系,但其非活性形式pS9-GSK-3β不表达于新生神经元内;
2.脑内GSK-3活性增高可特异性地引起成年大鼠海马齿状回的神经发生水平增高;
3. GSK-3主要通过促进细胞增殖使大鼠海马齿状回的新生神经元增多。
为观察tau蛋白的磷酸化水平与神经发生之间的相关性,我们采用免疫印迹的方法对WT处理的大鼠脑内tau蛋白的磷酸化水平进行了测定;接下来,为探讨磷酸化tau蛋白与神经元发育之间的关系,我们选取了出生1天(P1)、出生8天(P8)、1月龄(P30)及成年大鼠(Adult,3-4月龄)4个年龄段的大鼠脑片用于研究,分别用识别未成熟神经元的抗体DCX和NeuroD,识别磷酸化tau蛋白的抗体PS396, PT205和PT231以及识别非磷酸化tau蛋白的抗体tau-1对大鼠脑内齿状回和SVZ区未成熟神经元及tau蛋白的分布/表达随年龄增长的变化情况进行观察;最后,为明确成年大鼠脑内磷酸化/非磷酸化tau蛋白与未成熟神经元之间的关系,我们采用免疫荧光双标的方法对大鼠脑内齿状回和SVZ区tau蛋白与未成熟神经元的关系进行了观察。
结果显示:
1.通过侧脑室注射WT使脑内GSK-3活性增高,可使大鼠齿状回tau蛋白的磷酸化程度明显增高;
2.齿状回内DCX和NeuroD阳性细胞的分布与tau蛋白的表达均随着年龄的增长而明显减少,磷酸化tau蛋白的分布/表达与新生神经元之间存在明显的相关性;SVZ区内DCX的分布范围随年龄增长逐渐减小,但其表达强度和tau蛋白一起随着年龄的增长逐渐增加,并在成年后维持一定的强度;
3.成年大鼠脑内磷酸化tau蛋白与新生神经元之间存在明显的共定位关系。
我们的结果提示,GSK-3的活性增高可使成年动物海马区的神经发生水平明显增加,而磷酸化tau蛋白特异性地表达于未成熟神经元内,在新生神经元的发育中具有一定的作用。本研究为揭示AD患者脑内神经发生水平增高的机制提供了实验证据。
Neurogenesis persists in the adult mammalian brain and remains restricted to the subgranular zone (SGZ) of the dentate gyrus in hippocampus and the subventricular zone (SVZ) of the lateral ventricles in forebrain. Alzheimer’s disease (AD) is the most common neurodegenerative disease. Increased hippocampal neurogenesis has been observed in AD brain, but little is known about the mechanisms that result in enhanced neurogenesis in AD. Until now, none of current medications has been proved to cure AD efficiently. Stimulation of endogenous adult neurogenesis, which could produce more newborn neurons to replace old and dead ones to play normal functions, is a promising therapeutic target for this disease. Therefore, it is of great value to know about which factors could influence adult neurogenesis and elucidate the mechanisms that lead to enhanced neurogenesis in AD brain.
One of the major pathological features of AD brain is the presence of neurofibrillary tangles which is mainly composed of hyperphosphorylated microtubule associated protein tau. Deregulation of glycogen synthase kinase-3 (GSK-3) activity has been postulated to play an important role in AD, on the basis of its association with neurofibrillary tangles. Besides, GSK-3βand tau protein have been reported to have a role in the development of neurons. In the present study, we investigate the effect of GSK-3 activation on adult neurogenesis and examine the relationship between phosphorylated tau protein and immature neurons in the SGZ and SVZ.
To explore the possible involvement of GSK-3βin neurogenesis, we first performed double staining of GSK-3βwith immature neuronal markers in the SGZ and SVZ. Next, we injected WT into the left ventricle of rat brain to activate GSK-3βto investigate the effect of GSK-3βactivation on adult neurogenesis by immunohistochemical methods. To further confirm the role of GSK-3 on adult hippocampal neurogenesis, we injected different amounts of WT and used SB, a specific inhibitor of GSK-3, alone or together with WT to treat animals. At 3 days after the brain injection, animals were sacrificed to examine the level of neurogenesis by western blot analysis. To explore the effect of GSK-3 activation on the proliferation, survival and differentiation of newborn cells in the adult hippocampus, we injected intraperitoneally the rats with BrdU for 3 days, and then injected WT or NS, as a control, through lateral ventricle. The number of BrdU-labeled cells and phenotype of newborn cells in the SGZ region were estimated at different time points after the ventricle injection.
The results are shown as follows:
1. GSK-3βis widely expressed in the SGZ of dentate gyrus and the SVZ of forebrain. Total GSK-3βis colocalized with immature neurons in the SGZ and SVZ, while inactivate GSK-3βis dissociated from immature neurons in these two areas.
2. Activation of GSK-3 stimulates neurogenesis specifically in the dentate gyrus of hippocampus.
3. GSK-3 induced enhanced hippocampal neurogenesis mainly by facilitating cell proliferation.
To explore the relationship between tau phosphorylation and adult neurogenesis, we compared the level of tau phosphorylation in NS- and WT-treated animals. Next, we performed immunohistochemistry in the brain slices of newborn (P1), 8 days (P8), 30 days (P30) and 3-4 months old (adult) rats to examine the correlation between tau phosphorylation and neurogenesis during brain development. Antibodies DCX and NeuroD were used to examine the distribution of immature neurons in the dentate gyrus and SVZ, and PS396, PT205 and PT231 / Tau-1 were used to examine the expression of phosphorylated / unphosphorylated tau protein in these two regions. Finally, we performed double immunofluorescent staining of tau protein with immature neuronal markers in the SGZ and SVZ of adut rat brain to observe the relationship between tau protein and adult neurogenesis. The results are presented as below:
1. Activation of GSK-3 induced elevated level of tau phosphorylation in the dentate gyrus of rats.
2. Distribution of DCX- and NeuroD-positive cells is correlated with the expression of phosphorylated tau protein in the dentate gyrus during brain development. Though the distribution of DCX decreases significantly with aging, which differs from that of tau protein, the expression of both DCX and tau protein increases during development and remains at moderate levels when matures into adulthood.
3. Phosphorylated tau is colocalized with immature neurons in the SGZ and SVZ of adult rat brain.
These results suggest that activation of GSK-3 facilitates adult neurogenesis in the SGZ of rat hippocampus and phosphorylated tau protein plays a role in the development of adult born immature neurons. Our finding provides a possible mechanism that leads to the enhanced neurogenesis observed in the AD brains.
以过度磷酸化的微管相关蛋白tau为主要成分的神经原纤维缠结(neurofibrillary tangles, NFTs)是AD患者脑内主要的病理特征之一,糖原合酶激酶-3β(glycogen synthase kinase 3, GSK-3β)是导致tau蛋白过度磷酸化的关键激酶,与AD病变的发展具有密切的联系。此外,tau蛋白与GSK-3β在神经元的发育中也具有重要作用。本研究旨在通过观察GSK-3β活性增高对成年大鼠脑内神经发生的影响及磷酸化tau蛋白在SGZ区和SVZ区与新生神经元之间的关系,探讨AD患者脑内神经发生水平增高的可能机制。
为探讨GSK-3β与成年神经发生的关系,我们首先采用免疫荧光双标的技术对成年大鼠脑内SGZ区和SVZ区GSK-3β与未成熟神经元之间的关系进行了观察;接下来,为观察GSK-3β活性增高对成年神经发生的影响,我们将动物分为2组,通过侧脑室定位注射生理盐水(NS组)或PI3K特异性抑制剂wortmannin(WT组),并分别于术后不同时间点取材,采用免疫组化的方法对大鼠脑内神经发生的水平进行测定;为进一步明确GSK-3β对成年神经发生的作用,我们将动物分为5组,通过侧脑室注射分别给予10μl的NS、10μMWT、100μMWT、70μM的GSK-3β特异性抑制剂SB216763 ( SB )或100μMWT和70μM SB联合给药,术后3天取材,采用免疫印迹的方法对大鼠脑内神经发生的水平进行测定;为探讨GSK-3β活性增高对成年大鼠齿状回内细胞增殖、分化及存活的影响,我们在侧脑室给药前对大鼠进行连续3天的BrdU腹腔注射,标记此时处于增殖期的新生细胞,并于术后跟踪观察BrdU+细胞的数量改变及分化情况。
结果显示:
1. GSK-3β广泛分布于成年大鼠海马齿状回及前脑的室管膜下区,与新生神经元存在明显的共定位关系,但其非活性形式pS9-GSK-3β不表达于新生神经元内;
2.脑内GSK-3活性增高可特异性地引起成年大鼠海马齿状回的神经发生水平增高;
3. GSK-3主要通过促进细胞增殖使大鼠海马齿状回的新生神经元增多。
为观察tau蛋白的磷酸化水平与神经发生之间的相关性,我们采用免疫印迹的方法对WT处理的大鼠脑内tau蛋白的磷酸化水平进行了测定;接下来,为探讨磷酸化tau蛋白与神经元发育之间的关系,我们选取了出生1天(P1)、出生8天(P8)、1月龄(P30)及成年大鼠(Adult,3-4月龄)4个年龄段的大鼠脑片用于研究,分别用识别未成熟神经元的抗体DCX和NeuroD,识别磷酸化tau蛋白的抗体PS396, PT205和PT231以及识别非磷酸化tau蛋白的抗体tau-1对大鼠脑内齿状回和SVZ区未成熟神经元及tau蛋白的分布/表达随年龄增长的变化情况进行观察;最后,为明确成年大鼠脑内磷酸化/非磷酸化tau蛋白与未成熟神经元之间的关系,我们采用免疫荧光双标的方法对大鼠脑内齿状回和SVZ区tau蛋白与未成熟神经元的关系进行了观察。
结果显示:
1.通过侧脑室注射WT使脑内GSK-3活性增高,可使大鼠齿状回tau蛋白的磷酸化程度明显增高;
2.齿状回内DCX和NeuroD阳性细胞的分布与tau蛋白的表达均随着年龄的增长而明显减少,磷酸化tau蛋白的分布/表达与新生神经元之间存在明显的相关性;SVZ区内DCX的分布范围随年龄增长逐渐减小,但其表达强度和tau蛋白一起随着年龄的增长逐渐增加,并在成年后维持一定的强度;
3.成年大鼠脑内磷酸化tau蛋白与新生神经元之间存在明显的共定位关系。
我们的结果提示,GSK-3的活性增高可使成年动物海马区的神经发生水平明显增加,而磷酸化tau蛋白特异性地表达于未成熟神经元内,在新生神经元的发育中具有一定的作用。本研究为揭示AD患者脑内神经发生水平增高的机制提供了实验证据。
Neurogenesis persists in the adult mammalian brain and remains restricted to the subgranular zone (SGZ) of the dentate gyrus in hippocampus and the subventricular zone (SVZ) of the lateral ventricles in forebrain. Alzheimer’s disease (AD) is the most common neurodegenerative disease. Increased hippocampal neurogenesis has been observed in AD brain, but little is known about the mechanisms that result in enhanced neurogenesis in AD. Until now, none of current medications has been proved to cure AD efficiently. Stimulation of endogenous adult neurogenesis, which could produce more newborn neurons to replace old and dead ones to play normal functions, is a promising therapeutic target for this disease. Therefore, it is of great value to know about which factors could influence adult neurogenesis and elucidate the mechanisms that lead to enhanced neurogenesis in AD brain.
One of the major pathological features of AD brain is the presence of neurofibrillary tangles which is mainly composed of hyperphosphorylated microtubule associated protein tau. Deregulation of glycogen synthase kinase-3 (GSK-3) activity has been postulated to play an important role in AD, on the basis of its association with neurofibrillary tangles. Besides, GSK-3βand tau protein have been reported to have a role in the development of neurons. In the present study, we investigate the effect of GSK-3 activation on adult neurogenesis and examine the relationship between phosphorylated tau protein and immature neurons in the SGZ and SVZ.
To explore the possible involvement of GSK-3βin neurogenesis, we first performed double staining of GSK-3βwith immature neuronal markers in the SGZ and SVZ. Next, we injected WT into the left ventricle of rat brain to activate GSK-3βto investigate the effect of GSK-3βactivation on adult neurogenesis by immunohistochemical methods. To further confirm the role of GSK-3 on adult hippocampal neurogenesis, we injected different amounts of WT and used SB, a specific inhibitor of GSK-3, alone or together with WT to treat animals. At 3 days after the brain injection, animals were sacrificed to examine the level of neurogenesis by western blot analysis. To explore the effect of GSK-3 activation on the proliferation, survival and differentiation of newborn cells in the adult hippocampus, we injected intraperitoneally the rats with BrdU for 3 days, and then injected WT or NS, as a control, through lateral ventricle. The number of BrdU-labeled cells and phenotype of newborn cells in the SGZ region were estimated at different time points after the ventricle injection.
The results are shown as follows:
1. GSK-3βis widely expressed in the SGZ of dentate gyrus and the SVZ of forebrain. Total GSK-3βis colocalized with immature neurons in the SGZ and SVZ, while inactivate GSK-3βis dissociated from immature neurons in these two areas.
2. Activation of GSK-3 stimulates neurogenesis specifically in the dentate gyrus of hippocampus.
3. GSK-3 induced enhanced hippocampal neurogenesis mainly by facilitating cell proliferation.
To explore the relationship between tau phosphorylation and adult neurogenesis, we compared the level of tau phosphorylation in NS- and WT-treated animals. Next, we performed immunohistochemistry in the brain slices of newborn (P1), 8 days (P8), 30 days (P30) and 3-4 months old (adult) rats to examine the correlation between tau phosphorylation and neurogenesis during brain development. Antibodies DCX and NeuroD were used to examine the distribution of immature neurons in the dentate gyrus and SVZ, and PS396, PT205 and PT231 / Tau-1 were used to examine the expression of phosphorylated / unphosphorylated tau protein in these two regions. Finally, we performed double immunofluorescent staining of tau protein with immature neuronal markers in the SGZ and SVZ of adut rat brain to observe the relationship between tau protein and adult neurogenesis. The results are presented as below:
1. Activation of GSK-3 induced elevated level of tau phosphorylation in the dentate gyrus of rats.
2. Distribution of DCX- and NeuroD-positive cells is correlated with the expression of phosphorylated tau protein in the dentate gyrus during brain development. Though the distribution of DCX decreases significantly with aging, which differs from that of tau protein, the expression of both DCX and tau protein increases during development and remains at moderate levels when matures into adulthood.
3. Phosphorylated tau is colocalized with immature neurons in the SGZ and SVZ of adult rat brain.
These results suggest that activation of GSK-3 facilitates adult neurogenesis in the SGZ of rat hippocampus and phosphorylated tau protein plays a role in the development of adult born immature neurons. Our finding provides a possible mechanism that leads to the enhanced neurogenesis observed in the AD brains.
引文
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