PTEN在铝毒性实验性阿尔茨海默病小鼠模型发生发展中的变化
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摘要
目的:在铝毒性拟阿尔茨海默病(Alzheimer’s disease, AD)小鼠模型上,以小鼠学习记忆障碍以及脑组织出现老年斑(SP)及神经原纤维缠结(NFT)等AD特征性病理变化为指标反映AD样进展程度,从小鼠海马等脑组织中PTEN蛋白以及磷酸化PTEN蛋白水平、PTEN mRNA水平、PTEN样免疫阳性反应物表达与分布等研究层次,探索PTEN在AD样诱导发生发展过程中的动态变化及其与AD的关联,以深化理解AD发病机制,为AD的防治提供新的途径,为抗AD新药研发提供新的药物作用靶点。
方法:①采用小鼠侧脑室注射0.5% AlCl3溶液2μl,每天1次,连续5 d诱导出实验性AD模型,对照组注射等量的人工脑脊液;②末次侧脑室注射后第2天、第7天采用避暗试验,第23～30天采用Morris水迷宫试验检测模型小鼠学习记忆能力;③上述3个时间点行为学试验结束后,随即采用改良的硫磺素染色技术(Modified thioflavine S techniques,MTST)检测小鼠海马等脑组织内SP和NFT等形成情况,RT-PCR测定小鼠海马组织内PTEN mRNA水平,Western blotting法测定其PTEN蛋白和磷酸化PTEN蛋白水平;④同上方案制作另一批铝毒性拟AD小鼠模型,分别于末次侧脑室注射后第7、14、21、28、35天,以免疫组织化学法观测PTEN样免疫阳性反应物在小鼠海马等脑组织内的表达与分布。
结果:
1.铝毒性实验性AD小鼠模型的建立:①上述末次侧脑室注射后第2天,模型组小鼠相比对照组逃避潜伏期和错误次数未见明显差异;②侧脑室注射后第7天,对照组小鼠逃避潜伏期较第2天显著延长(P<0.001),错误次数减少;而模型组小鼠潜伏期未见明显变化,错误次数增加,双因素统计分析显示模型组小鼠逃避记忆能力随时间进行受铝毒的影响显著下降(铝毒处理和时间交互作用,P<0.05);③侧脑室注射后第23～30天,在Morris水迷宫试验中,模型组小鼠定向航行平均成绩显著低于对照组(P<0.001),空间探索目标象限滞留时间显著低于对照组(P<0.05),表明模型组小鼠空间学习记忆能力显著受损;④在上述3个时间点行为学试验结束后,每组立即取2～3只小鼠断头取脑,MTST染色可见于侧脑室注射后第30天模型组小鼠大脑颞区皮质有老年斑和神经原纤维缠结类似结构。
2.铝毒性拟AD小鼠海马组织中PTEN mRNA水平的变化:在上述3个时间点行为学试验结束后,每组立即取4～5只小鼠断头取脑,分离全海马并提取总RNA,行RT-PCR测定海马组织中PTEN mRNA水平,结果显示第2、7天模型组与对照组无明显差异,第30天模型组mRNA水平显著低于对照组(P<0.05,1-tailed)。
3.铝毒性拟AD小鼠海马组织中PTEN蛋白和磷酸化PTEN蛋白水平的变化:在上述3个时间点行为学试验结束后,每组立即取4～5只小鼠断头取脑,分离全海马行①Western blotting测定海马组织PTEN蛋白水平,结果见上述3个时间点模型组均略高于对照组,但无显著差异;②Western blotting测定海马组织中磷酸化PTEN-Ser380蛋白水平,侧脑室注射后第2、7天模型组与对照组未见明显差异,第30天模型组磷酸化PTEN-Ser380蛋白水平显著低于对照组(P<0.05)。
4.铝毒性拟AD小鼠发生发展过程中脑组织PTEN样免疫阳性反应物表达与分布的变化状况:①海马组织:镜下观察可见,PTEN样免疫阳性反应物在小鼠海马CA1、CA2、CA3锥体层细胞及齿状回颗粒细胞存在高丰度表达;上述侧脑室末次注射后第7、14、21、28、35天,模型组小鼠海马CA1区锥体层神经元内PTEN样免疫阳性反应强度相比对照组存在变化,而在CA2、CA3区锥体层细胞及齿状回颗粒细胞未见明显变化。以免疫组化专用分析软件选择测定CA1区锥体层灰度值,结果表明,侧脑室末次注射后第7天模型组小鼠海马CA1区锥体神经元PTEN样免疫阳性反应强度显著高于对照组(**P<0.01);第14天仍高于对照组(*P<0.05);第21、28天与对照组相比无显著差异;第35天显著低于对照组(*P<0.05)。②大脑皮质组织:镜下观察可见,PTEN样免疫阳性反应物在大脑皮质锥体神经元高丰度表达,颗粒层及多形细胞层弱阳性表达。上述侧脑室末次注射后第7、14、21、28、35天,模型组小鼠大脑皮质颞区第Ш层锥体神经元PTEN样免疫阳性反应强度相比对照组存在变化。以免疫组化专用分析软件选择测定大脑皮质颞区第Ш层锥体神经元灰度值,结果显示,模型组小鼠大脑皮质颞区第Ш层锥体神经元PTEN样免疫阳性反应强度呈阶段性变化,侧脑室末次注射后第7天模型组和对照组比较无显著差异;第14天模型组显著强于对照组(**P<0.01);第21、28和35天模型组均显著弱于对照组(*P<0.05)。
结论:
1.侧脑室注射AlCl3可致小鼠学习记忆能力显著受损,大脑颞区皮质在模型发展的后期可出现SPs和NFTs,提示铝毒性小鼠可作为拟AD动物研究模型,其发展呈进行性加重。
2.铝毒性拟AD小鼠发生发展后期,其海马组织PTEN mRNA水平、磷酸化PTEN蛋白水平显著下降。
3.在铝毒性拟AD小鼠发生发展过程中,PTEN在海马CA1区和大脑皮质颞区第Ш层锥体神经元内的表达呈现动态变化,发生期表达增强,而发展后期及形成期表达减弱。
Objective:In order to investigate the alteration of PTEN at different stages of mimic Alzheimer’s disease(AD), and to further speculate its role in AD, We made aluminum toxic mice model, judged the damage degree of the model mice by impairment of learning and memory in behavioral tests and pathological staining with SPs and NFTs, and detect PTEN protein level, phospho-PTEN protein level, PTEN mRNA level, and PTEN immunoreactivity and distribution in the hippocampus and brain cortex. These will be beneficial to understand the etio-pathological mechanism of AD and to find new strategies and targets for AD drug therapy.
Methods:①Infusion of 0.5% AlCl3 solution, 2μl/d,consecutively for 5 days, into the lateral cerebro-ventricles of the mice was used to produce the model, infusion of ACSF (artificial cerebrospinal fluid) for the control.②Passive avoidance response tests 2 and 7 days, and Morris water maze tasks 23～30 days after the last injection were used to identify the degrees of learning and memory impairment in the mice.③Immediately after the behavioral tests at the above three time points, MTST (Modified thioflavine S techniques) was used to detect the formation of SPs and NFTs in hippocampus and brain cortex, RT-PCR to detect PTEN mRNA expression and immunoblotting to detect protein levels of PTEN and pPTEN-Ser380 in hippocampus.④The same procedure was used to treat another crop of mice, and immunostaining to detect the distribution and intensity of PTEN in the hippocampus and brain cortex 7, 14, 21, 28, 35 days respectively after the last injection.
Results:
1.Aluminum toxic AD-like model:①The avoidance latencies and number errors had no significant difference between the model and the control 2 days post i.c.v..②The latencies of the control significantly prolonged at the 7th day post i.c.v. than that at the 2nd day post i.c.v. (P<0.001), and the error number decreased; the latencies of the model had no significant change but the error number increased; reflecting that the ability of passive avoidance of the model mice is deteriorating(interaction of treatment and time, P<0.05).③The mean performance record of the model was significantly worse than that of the control in place navigation test of Morris water maze task 23～30 days post i.c.v. (P<0.001); in spatial probe test, the lingering time of the model within the target quadrat was significantly shorter than that of the control(P<0.05), reflecting a severe impairment on learning and memory ability of the model mice.④2～3 mice of each group were decapitated immediately after the behavioral tests in the above three time points, and the brain sections of the model at the third time points (30 days post i.c.v.) stained by MTST showed SPs and NFT-like structures in regiones temporalis cortex.
2.PTEN mRNA levels of the hippocampus: 4～5 mice of each group were decapitated immediately after the behavioral tests in the above three time points, the complete hippocampuses were stripped out, and the total RNA was extracted; the mRNAs were reversely transcripted and the cDNAs were amplificated by PCR; the PTEN mRNA level of the model at the third time point (30 days post i.c.v.) was found significantly lower than that of the control(P<0.05, 1-tailed), but no significant difference was found between the model and the control at the first two time points.
3.Protein levels of PTEN and p-PTEN in the hippocampus: 4～5 mice of each group were decapitated immediately after the behavioral tests in the above three time points, the complete hippocampuses were stripped out and the protein levels of PTEN and pPTEN-Ser380 were detected by Western blotting.①No significant difference of PTEN protein level between the model and the control was found, but a slight increase of the model at the above three time points.②The protein level of pPTEN-Ser380 of the model at the third time point (30 days post i.c.v.) was found significantly lower than that of the control(P<0.05), but no significant difference between the model and the control at the first two time points.
4.Immuno-histochemistry staining: The same procedure is used to treat another crop of mice, which were then divided into the model and the control. 5 mice of each group respectively at the 7th, 14th, 21st, 28th, 35th day post i.c.v. were perfusion-fixed with 4% formaldehyde. Coronal sections of the brain were made by Microtome Cryostat and immunostained with anti-PTEN as the primary antibody, and streptomycin-anti-biotin (SP) kite and 3’3’diaminobenzidine (DAB) was used to present the staining. The analysis results of immunoreactive intensities showed that①PTEN is abundantly expressed in the pyramidal neurons of the CA1, CA2, CA3 regions of the hippocampus and in the granule cells of the dentate gyrus; the pyramidal neurons of the CA1 region in the hippocampuses of the model showed significantly higher immunoreactive intensity than that of the control at the 7th day post i.c.v. (P<0.05); it was still higher than that of the control at the 14th day post i.c.v.(P<0.05); no significant difference was found at the 21st and 28th day post i.c.v.; but the immunoreactive intensity of the model was significantly lower than that of the control at the 35th day post i.c.v.(P<0.05);②PTEN is abundantly expressed in pyramidal neurons of brain cortex, and weak immunoreactivity was also seen in other brain cellular stratums; the immunoreactive intensity of the lamina pyramidalis in regiones temporalis of the model mice displayed a dynamic alteration; no significant differnence between the model and control at the 7th day post i.c.v., but a significantly higher immunoreactive intensity was seen of the model than that of matched control at the 14th day post i.c.v.(P<0.01); significantly lower intensities of the model than that of matched control were found at the 28, 35 days post i.c.v.(P<0.05).
Conclusion:
1. The experimental AD-like mice model with AlCl3 i.c.v. displayed a progressive decline in the ability of learning and memory, with SPs and NFTs-like structure appearing in the regiones temporalis cortex at the end stage. So the model successfully simulated the learning and memory impairment and pathological changes in AD, figuring out the initiative, development and formation of an AD-like process.
2. In the anaphase of the aluminum toxic mice, the PTEN mRNA level and phospho-PTEN protein level significantly decreased.
3. In the progression of the model induced, PTEN might have a dynamic alteration in stratum pyramidale neurons of the hippocampal CA1 regions and in layer of medium-sized pyramidal cells in regiones temporalis cortex, where it arised at the initiative stage and then descended in the developmental and formative stages until to a degree significantly lower than that of matched control at the end stage.
方法:①采用小鼠侧脑室注射0.5% AlCl3溶液2μl,每天1次,连续5 d诱导出实验性AD模型,对照组注射等量的人工脑脊液;②末次侧脑室注射后第2天、第7天采用避暗试验,第23～30天采用Morris水迷宫试验检测模型小鼠学习记忆能力;③上述3个时间点行为学试验结束后,随即采用改良的硫磺素染色技术(Modified thioflavine S techniques,MTST)检测小鼠海马等脑组织内SP和NFT等形成情况,RT-PCR测定小鼠海马组织内PTEN mRNA水平,Western blotting法测定其PTEN蛋白和磷酸化PTEN蛋白水平;④同上方案制作另一批铝毒性拟AD小鼠模型,分别于末次侧脑室注射后第7、14、21、28、35天,以免疫组织化学法观测PTEN样免疫阳性反应物在小鼠海马等脑组织内的表达与分布。
结果:
1.铝毒性实验性AD小鼠模型的建立:①上述末次侧脑室注射后第2天,模型组小鼠相比对照组逃避潜伏期和错误次数未见明显差异;②侧脑室注射后第7天,对照组小鼠逃避潜伏期较第2天显著延长(P<0.001),错误次数减少;而模型组小鼠潜伏期未见明显变化,错误次数增加,双因素统计分析显示模型组小鼠逃避记忆能力随时间进行受铝毒的影响显著下降(铝毒处理和时间交互作用,P<0.05);③侧脑室注射后第23～30天,在Morris水迷宫试验中,模型组小鼠定向航行平均成绩显著低于对照组(P<0.001),空间探索目标象限滞留时间显著低于对照组(P<0.05),表明模型组小鼠空间学习记忆能力显著受损;④在上述3个时间点行为学试验结束后,每组立即取2～3只小鼠断头取脑,MTST染色可见于侧脑室注射后第30天模型组小鼠大脑颞区皮质有老年斑和神经原纤维缠结类似结构。
2.铝毒性拟AD小鼠海马组织中PTEN mRNA水平的变化:在上述3个时间点行为学试验结束后,每组立即取4～5只小鼠断头取脑,分离全海马并提取总RNA,行RT-PCR测定海马组织中PTEN mRNA水平,结果显示第2、7天模型组与对照组无明显差异,第30天模型组mRNA水平显著低于对照组(P<0.05,1-tailed)。
3.铝毒性拟AD小鼠海马组织中PTEN蛋白和磷酸化PTEN蛋白水平的变化:在上述3个时间点行为学试验结束后,每组立即取4～5只小鼠断头取脑,分离全海马行①Western blotting测定海马组织PTEN蛋白水平,结果见上述3个时间点模型组均略高于对照组,但无显著差异;②Western blotting测定海马组织中磷酸化PTEN-Ser380蛋白水平,侧脑室注射后第2、7天模型组与对照组未见明显差异,第30天模型组磷酸化PTEN-Ser380蛋白水平显著低于对照组(P<0.05)。
4.铝毒性拟AD小鼠发生发展过程中脑组织PTEN样免疫阳性反应物表达与分布的变化状况:①海马组织:镜下观察可见,PTEN样免疫阳性反应物在小鼠海马CA1、CA2、CA3锥体层细胞及齿状回颗粒细胞存在高丰度表达;上述侧脑室末次注射后第7、14、21、28、35天,模型组小鼠海马CA1区锥体层神经元内PTEN样免疫阳性反应强度相比对照组存在变化,而在CA2、CA3区锥体层细胞及齿状回颗粒细胞未见明显变化。以免疫组化专用分析软件选择测定CA1区锥体层灰度值,结果表明,侧脑室末次注射后第7天模型组小鼠海马CA1区锥体神经元PTEN样免疫阳性反应强度显著高于对照组(**P<0.01);第14天仍高于对照组(*P<0.05);第21、28天与对照组相比无显著差异;第35天显著低于对照组(*P<0.05)。②大脑皮质组织:镜下观察可见,PTEN样免疫阳性反应物在大脑皮质锥体神经元高丰度表达,颗粒层及多形细胞层弱阳性表达。上述侧脑室末次注射后第7、14、21、28、35天,模型组小鼠大脑皮质颞区第Ш层锥体神经元PTEN样免疫阳性反应强度相比对照组存在变化。以免疫组化专用分析软件选择测定大脑皮质颞区第Ш层锥体神经元灰度值,结果显示,模型组小鼠大脑皮质颞区第Ш层锥体神经元PTEN样免疫阳性反应强度呈阶段性变化,侧脑室末次注射后第7天模型组和对照组比较无显著差异;第14天模型组显著强于对照组(**P<0.01);第21、28和35天模型组均显著弱于对照组(*P<0.05)。
结论:
1.侧脑室注射AlCl3可致小鼠学习记忆能力显著受损,大脑颞区皮质在模型发展的后期可出现SPs和NFTs,提示铝毒性小鼠可作为拟AD动物研究模型,其发展呈进行性加重。
2.铝毒性拟AD小鼠发生发展后期,其海马组织PTEN mRNA水平、磷酸化PTEN蛋白水平显著下降。
3.在铝毒性拟AD小鼠发生发展过程中,PTEN在海马CA1区和大脑皮质颞区第Ш层锥体神经元内的表达呈现动态变化,发生期表达增强,而发展后期及形成期表达减弱。
Objective:In order to investigate the alteration of PTEN at different stages of mimic Alzheimer’s disease(AD), and to further speculate its role in AD, We made aluminum toxic mice model, judged the damage degree of the model mice by impairment of learning and memory in behavioral tests and pathological staining with SPs and NFTs, and detect PTEN protein level, phospho-PTEN protein level, PTEN mRNA level, and PTEN immunoreactivity and distribution in the hippocampus and brain cortex. These will be beneficial to understand the etio-pathological mechanism of AD and to find new strategies and targets for AD drug therapy.
Methods:①Infusion of 0.5% AlCl3 solution, 2μl/d,consecutively for 5 days, into the lateral cerebro-ventricles of the mice was used to produce the model, infusion of ACSF (artificial cerebrospinal fluid) for the control.②Passive avoidance response tests 2 and 7 days, and Morris water maze tasks 23～30 days after the last injection were used to identify the degrees of learning and memory impairment in the mice.③Immediately after the behavioral tests at the above three time points, MTST (Modified thioflavine S techniques) was used to detect the formation of SPs and NFTs in hippocampus and brain cortex, RT-PCR to detect PTEN mRNA expression and immunoblotting to detect protein levels of PTEN and pPTEN-Ser380 in hippocampus.④The same procedure was used to treat another crop of mice, and immunostaining to detect the distribution and intensity of PTEN in the hippocampus and brain cortex 7, 14, 21, 28, 35 days respectively after the last injection.
Results:
1.Aluminum toxic AD-like model:①The avoidance latencies and number errors had no significant difference between the model and the control 2 days post i.c.v..②The latencies of the control significantly prolonged at the 7th day post i.c.v. than that at the 2nd day post i.c.v. (P<0.001), and the error number decreased; the latencies of the model had no significant change but the error number increased; reflecting that the ability of passive avoidance of the model mice is deteriorating(interaction of treatment and time, P<0.05).③The mean performance record of the model was significantly worse than that of the control in place navigation test of Morris water maze task 23～30 days post i.c.v. (P<0.001); in spatial probe test, the lingering time of the model within the target quadrat was significantly shorter than that of the control(P<0.05), reflecting a severe impairment on learning and memory ability of the model mice.④2～3 mice of each group were decapitated immediately after the behavioral tests in the above three time points, and the brain sections of the model at the third time points (30 days post i.c.v.) stained by MTST showed SPs and NFT-like structures in regiones temporalis cortex.
2.PTEN mRNA levels of the hippocampus: 4～5 mice of each group were decapitated immediately after the behavioral tests in the above three time points, the complete hippocampuses were stripped out, and the total RNA was extracted; the mRNAs were reversely transcripted and the cDNAs were amplificated by PCR; the PTEN mRNA level of the model at the third time point (30 days post i.c.v.) was found significantly lower than that of the control(P<0.05, 1-tailed), but no significant difference was found between the model and the control at the first two time points.
3.Protein levels of PTEN and p-PTEN in the hippocampus: 4～5 mice of each group were decapitated immediately after the behavioral tests in the above three time points, the complete hippocampuses were stripped out and the protein levels of PTEN and pPTEN-Ser380 were detected by Western blotting.①No significant difference of PTEN protein level between the model and the control was found, but a slight increase of the model at the above three time points.②The protein level of pPTEN-Ser380 of the model at the third time point (30 days post i.c.v.) was found significantly lower than that of the control(P<0.05), but no significant difference between the model and the control at the first two time points.
4.Immuno-histochemistry staining: The same procedure is used to treat another crop of mice, which were then divided into the model and the control. 5 mice of each group respectively at the 7th, 14th, 21st, 28th, 35th day post i.c.v. were perfusion-fixed with 4% formaldehyde. Coronal sections of the brain were made by Microtome Cryostat and immunostained with anti-PTEN as the primary antibody, and streptomycin-anti-biotin (SP) kite and 3’3’diaminobenzidine (DAB) was used to present the staining. The analysis results of immunoreactive intensities showed that①PTEN is abundantly expressed in the pyramidal neurons of the CA1, CA2, CA3 regions of the hippocampus and in the granule cells of the dentate gyrus; the pyramidal neurons of the CA1 region in the hippocampuses of the model showed significantly higher immunoreactive intensity than that of the control at the 7th day post i.c.v. (P<0.05); it was still higher than that of the control at the 14th day post i.c.v.(P<0.05); no significant difference was found at the 21st and 28th day post i.c.v.; but the immunoreactive intensity of the model was significantly lower than that of the control at the 35th day post i.c.v.(P<0.05);②PTEN is abundantly expressed in pyramidal neurons of brain cortex, and weak immunoreactivity was also seen in other brain cellular stratums; the immunoreactive intensity of the lamina pyramidalis in regiones temporalis of the model mice displayed a dynamic alteration; no significant differnence between the model and control at the 7th day post i.c.v., but a significantly higher immunoreactive intensity was seen of the model than that of matched control at the 14th day post i.c.v.(P<0.01); significantly lower intensities of the model than that of matched control were found at the 28, 35 days post i.c.v.(P<0.05).
Conclusion:
1. The experimental AD-like mice model with AlCl3 i.c.v. displayed a progressive decline in the ability of learning and memory, with SPs and NFTs-like structure appearing in the regiones temporalis cortex at the end stage. So the model successfully simulated the learning and memory impairment and pathological changes in AD, figuring out the initiative, development and formation of an AD-like process.
2. In the anaphase of the aluminum toxic mice, the PTEN mRNA level and phospho-PTEN protein level significantly decreased.
3. In the progression of the model induced, PTEN might have a dynamic alteration in stratum pyramidale neurons of the hippocampal CA1 regions and in layer of medium-sized pyramidal cells in regiones temporalis cortex, where it arised at the initiative stage and then descended in the developmental and formative stages until to a degree significantly lower than that of matched control at the end stage.
引文
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