神经甾体激素硫化孕烯醇酮和脱氢表雄酮对AD脑神经再生的影响
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摘要
背景
在成年啮齿类和某些哺乳动物脑内,存在神经干细胞和神经前体细胞,这类细胞具有终生自我更新的能力,可以分化为神经细胞——成年神经发生(Neurogenesis)。在海马齿状回,这些新生神经元显示了与成熟颗粒细胞相同的形态和功能特征,能与CA3区神经元和内嗅皮层的传入纤维建立突触联系,诱发突触传递和可塑性。特别是海马齿状回的神经发生已被证实与空间认知功能密切相关,如新生神经元数量增多能提高学习记忆功能,而阻碍成年神经发生则造成记忆功能减退。因此,成年海马的新生神经元被认为能取代自然老化或病变的神经元,最大限度地维护脑的结构和功能。
阿尔茨海默病(Alzheimer’s disease, AD)是一种以进行性认知功能障碍为特征的神经退行性疾病。新生神经元是否能替代病变的神经元——神经再生,改善认知功能障碍已成为目前AD研究的一个新焦点。神经发生过程主要包括干细胞增殖、前体细胞存活和分化、新生神经元的成熟、突触形成和神经回路整合4个阶段。研究发现,AD患者脑内海马的干细胞增殖有增加的趋势。在APP转基因的小鼠,前体细胞向神经元的分化比例明显减少,同时新生神经元的存活率显著降低。我们的早期研究已报道,β-淀粉肽(β-amyloid, Aβ)25-35片段(Aβ25-35)侧脑室注射能损害新生神经元的突起生长,导致新生神经细胞死亡。这些结果都提示,AD脑神经再生过程的破坏可能是认知功能进行性减退的重要病理机制之一。但是,迄今有关AD脑的神经再生过程仍然缺乏系统性的研究。
在啮齿类动物,中枢神经元能自身合成甾体激素——神经甾体激素。硫化孕烯醇酮(pregnenolone sulfat, PREGS)和脱氢表雄酮(dehydroepiandrosterone, DHEA)是中枢神经系统中含量最丰富、活性最强的神经甾体激素。早期的研究报道,DHEA能促进大鼠海马齿状回新生神经元的存活,也可以拮抗皮质酮抑制神经干细胞增殖的作用。我们的研究已报道PREGS能促进成年大鼠海马齿状回的神经发生,能增强新生神经元的传入兴奋性(增加新生神经元的突触前谷氨酸释放)。临床研究发现,与同年龄非认知障碍的人群相比,AD患者脑内PREGS浓度明显降低,而DHEA的浓度却有增加趋势。AD脑内PREGS和DHEA浓度的变化是否影响神经再生的过程,迄今仍未见有明确的报道。
目的
1、采用APPswe/PS1dE9转基因小鼠(简称APP/PS1小鼠),确定Aβ过表达对海马齿状回神经再生过程(包括增殖、分化、迁移、突起生长和成熟)的影响;
2、探讨PREGS和DHEA的处理是否对Aβ损害海马神经再生有作用。
实验方法
1、AD动物模型的准备:将生后8月龄APP/PS1小鼠作为AD的实验动物模型。用剪尾提取DNA进行PCR扩增的方法来鉴定基因型。用Aβ免疫组织化学染色的方法,检测APP/PS1小鼠脑的老年斑生成;用“Morris”水迷宫实验,检查APP/PS1小鼠的空间记忆功能。
2、检测小鼠海马齿状回的神经再生过程(包括增殖、分化、迁移、突起生长和成熟)。用BrdU(5-溴-2-脱氧尿嘧啶核苷)连续12天皮下注射标记有丝分裂的细胞。分别在BrdU末次注射后24小时,第14天和第28天,进行BrdU免疫组织化学染色,分别进行海马齿状回1天龄-BrdU阳性细胞(BrdU+细胞)、14天龄-BrdU+细胞和28天龄-BrdU+细胞的计数。
3、分别用神经特异性核蛋白(Neuron-specific protein, NeuN)或胶质纤维酸性蛋白(Glial fibrillary acidic protein, GFAP)与BrdU双标记免疫荧光染色,检测海马齿状回新生神经细胞的分化和成熟。
4、采用增殖细胞核抗原(Proliferating cell nuclear antigen, Ki67)染色,检测海马齿状回神经干细胞的增殖。
5、用doublecortin (DCX)免疫组织染色,检测新生神经元突起的长度和密度。
6、分别给8月龄APP/PS1小鼠进行PREGS或DHEA处理,探讨和比较两种神经甾体激素对APP/PS1小鼠海马齿状回神经再生过程(包括增殖、分化、迁移、突起生长和成熟)的影响;
7、用Morris水迷宫实验法检测空间学习记忆功能。探讨PREGS或DHEA改变APP/PS1小鼠的神经再生对空间认知障碍的作用。
结果
1、与同窝或同周龄的野生型小鼠相比,8月龄APP/PS1小鼠的大脑皮层和海马区域出现大量的老年斑,并表现水迷宫登台潜伏期的明显延长;
2、与对照组小鼠相比,APP/PS1小鼠海马齿状回的1天龄BrdU+细胞数量增加约30%,而14天龄BrdU+细胞数量两组之间无统计学意义,但是28天龄BrdU+细胞数量减少约50%;
3、与对照组小鼠相比,APP/PS1小鼠海马齿状回的Ki67免疫阳性(Ki67+)细胞数量显著增加;但是DCX免疫阳性(DCX+)细胞的突起长度显著减小,而DCX+细胞数量两组之间无统计学差异;BrdU和NeuN免疫反应双阳性(BrdU+/NeuN+)细胞数量显著减少,而BrdU和GFAP免疫反应双阳性(BrdU+/GFAP+)细胞数量两组之间无统计学差异。
4、PREGS和DHEA并不影响APP/PS1小鼠的神经干细胞的过增殖;但是PREGS和DHEA保护APP/PS1小鼠新生神经元的突起生长;而只有PREGS能保护APP/PS1小鼠新生神经元的存活,导致BrdU+/NeuN+细胞增加;
5、PREGS能改善APP/PS1小鼠水迷宫登台潜伏期的延长。
结论
1、Aβ刺激海马齿状回干细胞的增殖,但是不影响神经前体细胞的分化。Aβ损害新生神经元的突起生长和新生神经元的存活,导致成熟的新生神经元减少。
2、PREGS或DHEA能保护APP/PS1小鼠海马新生神经元的突起生长,但是只有PREGS能保护APP/PS1小鼠海马新生神经元的存活,并改善APP/PS1小鼠的空间认知功能。本论文的结果提示,AD脑的PREGS水平降低可能与神经再生障碍的发生有关;PREGS治疗有可能缓解AD患者的痴呆症状。
Introduction
It is widely accepted that the mammalian brain produces continuously newborn neurons in the hippocampal dentate gyrus (DG) throughout the adult life with a comparative rate as that of mature granular cells death. It has been implicated that the adult hippocampal neurogenesis plays an important role in the regulation of cognition. Hippocampal neurogenesis decreases drastically during aging in rodents, and this decline in neurogenic capacity has been suggested to underlie cognitive deterioration in aged animals. Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by selective damage in the cognitive function. The number of immature newborn neurons is increased in the hippocampus of AD patients and model with Swedish and Indiana amyloid precursor protein mutations. It is also known that the overproduction and subsequent aggregation of Aβlimit the survival of hippocampal newborn neurons. Thus, it is speculated that the impaired hippocampal neurogenesis might be one of the causes for cognitive deterioration in AD.
Neurosteroids dehydroepiandrosterone (DHEA) and pregnenolone sulfate (PREGS) are synthesized in the rodent brain independently of peripheral glandular sources. Previous study reported that DHEA could increase the number of newly generated neurons in rat hippocampal dentate gyrus and antagonize the suppressive effect of corticosterone on neuronal precursor proliferation. PREGS is also known to facilitate the production of new neurons, which takes place during early development and throughout life within specific brain regions such as the dentate gyrus of the hippocampus. Specially, PREGS influences the developmental processes of neural circuit formation through strengthening immature excitatory synapses in the hippocampus. Even in old rats, PREGS stimulates neurogenesis in the dentate gyrus. Recently, correlation between the decreased level of brain neurosteroids and neuronal degeneration in AD patients has been paid close attention. Interestingly, the level of DHEA increases in AD patients, although synthesis of brain DHEA declines with normal aging. The level of PREGS decreases in AD patients’brain in comparison with that of age-matched non-demented controls.
Objective
(1) To determine the changes in the hippocampal neurogenesis in male mice over-expressing amyloid precursor protein (APP) and presenilin-1 (PS1) (APP/PS1 mice).
(2) To explore the effects of neurosteroids PREGS or DHEA on neurogenesis and the impairment of spatial memory in APP/PS1 mice.
Materials and Methods
1. Preparation of an animal model: APP/PS1 mice were obtained from Jackson Laboratory (Bar Harbor, ME, USA). The genotyping for APP/PS1 mice was performed by polymerase chain reaction (PCR) method recommended by the Jackson Laboratory, using tissue samples from tail of mice. The APP/PS1 mice were generated by crossing transgenic mice with B6C3F1 mice and characterized as described previously.
2. Drug administration: Proliferating cells were labeled by bromodeoxyuridine (BrdU). DHEA and PREGS at 20 mg/kg concentration were injected (i.p.) once daily.
3. Immunohistochemistry: Aβ、Ki67、BrdU and Doublecortin immuno-reactivities were visualized by avidin-biotin horseradish peroxidase complex. BrdU and NeuN or GFAP double immunostaining. And quantitative evaluation of immuno-positive cells.
4. Behavioral Analysis: Morris water maze task.
Results
1、8-month-old APP/PS1 mice showed the extracellular deposition of Aβ, amyloid plaques in hippocampus and spatial memory impairment
2、Comparison with control rats, in the hippocampal dentate gyrus of 8-month-old APP/PS1 mice the proliferation of progenitor cells increased, while the neurite growth and survival of newborn neuronal cells were markedly impaired.
3、Either PREGS or DHEA could perfectly rescue the hypoplastic neurite of newborn neurons in APP/PS1 mice, whereas neither of them affected the over-proliferation of progenitor cells.
4、Notably, PREGS but not DHEA could protect the survival of newborn neuronal cells to approach maturation in APP/PS1 mice.
5、The protection of hippocampal neurogenesis in APP/PS1 mice treated with PREGS was accompanied with an improvement of spatial learning and memory.
Conclusion
The present study provides in vivo evidence that the treatment with either PREGS or DHEA could rescue the impaired neurite of newborn neurons, but only PREGS perfectly protected the survival and maturation of newly generated neuronal cells in APP/PS1 mice. The protection of PREGS against Aβ-impaired neurogenesis had a definite effect on improving cognitive deterioration in APP/PS1 mice.
在成年啮齿类和某些哺乳动物脑内,存在神经干细胞和神经前体细胞,这类细胞具有终生自我更新的能力,可以分化为神经细胞——成年神经发生(Neurogenesis)。在海马齿状回,这些新生神经元显示了与成熟颗粒细胞相同的形态和功能特征,能与CA3区神经元和内嗅皮层的传入纤维建立突触联系,诱发突触传递和可塑性。特别是海马齿状回的神经发生已被证实与空间认知功能密切相关,如新生神经元数量增多能提高学习记忆功能,而阻碍成年神经发生则造成记忆功能减退。因此,成年海马的新生神经元被认为能取代自然老化或病变的神经元,最大限度地维护脑的结构和功能。
阿尔茨海默病(Alzheimer’s disease, AD)是一种以进行性认知功能障碍为特征的神经退行性疾病。新生神经元是否能替代病变的神经元——神经再生,改善认知功能障碍已成为目前AD研究的一个新焦点。神经发生过程主要包括干细胞增殖、前体细胞存活和分化、新生神经元的成熟、突触形成和神经回路整合4个阶段。研究发现,AD患者脑内海马的干细胞增殖有增加的趋势。在APP转基因的小鼠,前体细胞向神经元的分化比例明显减少,同时新生神经元的存活率显著降低。我们的早期研究已报道,β-淀粉肽(β-amyloid, Aβ)25-35片段(Aβ25-35)侧脑室注射能损害新生神经元的突起生长,导致新生神经细胞死亡。这些结果都提示,AD脑神经再生过程的破坏可能是认知功能进行性减退的重要病理机制之一。但是,迄今有关AD脑的神经再生过程仍然缺乏系统性的研究。
在啮齿类动物,中枢神经元能自身合成甾体激素——神经甾体激素。硫化孕烯醇酮(pregnenolone sulfat, PREGS)和脱氢表雄酮(dehydroepiandrosterone, DHEA)是中枢神经系统中含量最丰富、活性最强的神经甾体激素。早期的研究报道,DHEA能促进大鼠海马齿状回新生神经元的存活,也可以拮抗皮质酮抑制神经干细胞增殖的作用。我们的研究已报道PREGS能促进成年大鼠海马齿状回的神经发生,能增强新生神经元的传入兴奋性(增加新生神经元的突触前谷氨酸释放)。临床研究发现,与同年龄非认知障碍的人群相比,AD患者脑内PREGS浓度明显降低,而DHEA的浓度却有增加趋势。AD脑内PREGS和DHEA浓度的变化是否影响神经再生的过程,迄今仍未见有明确的报道。
目的
1、采用APPswe/PS1dE9转基因小鼠(简称APP/PS1小鼠),确定Aβ过表达对海马齿状回神经再生过程(包括增殖、分化、迁移、突起生长和成熟)的影响;
2、探讨PREGS和DHEA的处理是否对Aβ损害海马神经再生有作用。
实验方法
1、AD动物模型的准备:将生后8月龄APP/PS1小鼠作为AD的实验动物模型。用剪尾提取DNA进行PCR扩增的方法来鉴定基因型。用Aβ免疫组织化学染色的方法,检测APP/PS1小鼠脑的老年斑生成;用“Morris”水迷宫实验,检查APP/PS1小鼠的空间记忆功能。
2、检测小鼠海马齿状回的神经再生过程(包括增殖、分化、迁移、突起生长和成熟)。用BrdU(5-溴-2-脱氧尿嘧啶核苷)连续12天皮下注射标记有丝分裂的细胞。分别在BrdU末次注射后24小时,第14天和第28天,进行BrdU免疫组织化学染色,分别进行海马齿状回1天龄-BrdU阳性细胞(BrdU+细胞)、14天龄-BrdU+细胞和28天龄-BrdU+细胞的计数。
3、分别用神经特异性核蛋白(Neuron-specific protein, NeuN)或胶质纤维酸性蛋白(Glial fibrillary acidic protein, GFAP)与BrdU双标记免疫荧光染色,检测海马齿状回新生神经细胞的分化和成熟。
4、采用增殖细胞核抗原(Proliferating cell nuclear antigen, Ki67)染色,检测海马齿状回神经干细胞的增殖。
5、用doublecortin (DCX)免疫组织染色,检测新生神经元突起的长度和密度。
6、分别给8月龄APP/PS1小鼠进行PREGS或DHEA处理,探讨和比较两种神经甾体激素对APP/PS1小鼠海马齿状回神经再生过程(包括增殖、分化、迁移、突起生长和成熟)的影响;
7、用Morris水迷宫实验法检测空间学习记忆功能。探讨PREGS或DHEA改变APP/PS1小鼠的神经再生对空间认知障碍的作用。
结果
1、与同窝或同周龄的野生型小鼠相比,8月龄APP/PS1小鼠的大脑皮层和海马区域出现大量的老年斑,并表现水迷宫登台潜伏期的明显延长;
2、与对照组小鼠相比,APP/PS1小鼠海马齿状回的1天龄BrdU+细胞数量增加约30%,而14天龄BrdU+细胞数量两组之间无统计学意义,但是28天龄BrdU+细胞数量减少约50%;
3、与对照组小鼠相比,APP/PS1小鼠海马齿状回的Ki67免疫阳性(Ki67+)细胞数量显著增加;但是DCX免疫阳性(DCX+)细胞的突起长度显著减小,而DCX+细胞数量两组之间无统计学差异;BrdU和NeuN免疫反应双阳性(BrdU+/NeuN+)细胞数量显著减少,而BrdU和GFAP免疫反应双阳性(BrdU+/GFAP+)细胞数量两组之间无统计学差异。
4、PREGS和DHEA并不影响APP/PS1小鼠的神经干细胞的过增殖;但是PREGS和DHEA保护APP/PS1小鼠新生神经元的突起生长;而只有PREGS能保护APP/PS1小鼠新生神经元的存活,导致BrdU+/NeuN+细胞增加;
5、PREGS能改善APP/PS1小鼠水迷宫登台潜伏期的延长。
结论
1、Aβ刺激海马齿状回干细胞的增殖,但是不影响神经前体细胞的分化。Aβ损害新生神经元的突起生长和新生神经元的存活,导致成熟的新生神经元减少。
2、PREGS或DHEA能保护APP/PS1小鼠海马新生神经元的突起生长,但是只有PREGS能保护APP/PS1小鼠海马新生神经元的存活,并改善APP/PS1小鼠的空间认知功能。本论文的结果提示,AD脑的PREGS水平降低可能与神经再生障碍的发生有关;PREGS治疗有可能缓解AD患者的痴呆症状。
Introduction
It is widely accepted that the mammalian brain produces continuously newborn neurons in the hippocampal dentate gyrus (DG) throughout the adult life with a comparative rate as that of mature granular cells death. It has been implicated that the adult hippocampal neurogenesis plays an important role in the regulation of cognition. Hippocampal neurogenesis decreases drastically during aging in rodents, and this decline in neurogenic capacity has been suggested to underlie cognitive deterioration in aged animals. Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by selective damage in the cognitive function. The number of immature newborn neurons is increased in the hippocampus of AD patients and model with Swedish and Indiana amyloid precursor protein mutations. It is also known that the overproduction and subsequent aggregation of Aβlimit the survival of hippocampal newborn neurons. Thus, it is speculated that the impaired hippocampal neurogenesis might be one of the causes for cognitive deterioration in AD.
Neurosteroids dehydroepiandrosterone (DHEA) and pregnenolone sulfate (PREGS) are synthesized in the rodent brain independently of peripheral glandular sources. Previous study reported that DHEA could increase the number of newly generated neurons in rat hippocampal dentate gyrus and antagonize the suppressive effect of corticosterone on neuronal precursor proliferation. PREGS is also known to facilitate the production of new neurons, which takes place during early development and throughout life within specific brain regions such as the dentate gyrus of the hippocampus. Specially, PREGS influences the developmental processes of neural circuit formation through strengthening immature excitatory synapses in the hippocampus. Even in old rats, PREGS stimulates neurogenesis in the dentate gyrus. Recently, correlation between the decreased level of brain neurosteroids and neuronal degeneration in AD patients has been paid close attention. Interestingly, the level of DHEA increases in AD patients, although synthesis of brain DHEA declines with normal aging. The level of PREGS decreases in AD patients’brain in comparison with that of age-matched non-demented controls.
Objective
(1) To determine the changes in the hippocampal neurogenesis in male mice over-expressing amyloid precursor protein (APP) and presenilin-1 (PS1) (APP/PS1 mice).
(2) To explore the effects of neurosteroids PREGS or DHEA on neurogenesis and the impairment of spatial memory in APP/PS1 mice.
Materials and Methods
1. Preparation of an animal model: APP/PS1 mice were obtained from Jackson Laboratory (Bar Harbor, ME, USA). The genotyping for APP/PS1 mice was performed by polymerase chain reaction (PCR) method recommended by the Jackson Laboratory, using tissue samples from tail of mice. The APP/PS1 mice were generated by crossing transgenic mice with B6C3F1 mice and characterized as described previously.
2. Drug administration: Proliferating cells were labeled by bromodeoxyuridine (BrdU). DHEA and PREGS at 20 mg/kg concentration were injected (i.p.) once daily.
3. Immunohistochemistry: Aβ、Ki67、BrdU and Doublecortin immuno-reactivities were visualized by avidin-biotin horseradish peroxidase complex. BrdU and NeuN or GFAP double immunostaining. And quantitative evaluation of immuno-positive cells.
4. Behavioral Analysis: Morris water maze task.
Results
1、8-month-old APP/PS1 mice showed the extracellular deposition of Aβ, amyloid plaques in hippocampus and spatial memory impairment
2、Comparison with control rats, in the hippocampal dentate gyrus of 8-month-old APP/PS1 mice the proliferation of progenitor cells increased, while the neurite growth and survival of newborn neuronal cells were markedly impaired.
3、Either PREGS or DHEA could perfectly rescue the hypoplastic neurite of newborn neurons in APP/PS1 mice, whereas neither of them affected the over-proliferation of progenitor cells.
4、Notably, PREGS but not DHEA could protect the survival of newborn neuronal cells to approach maturation in APP/PS1 mice.
5、The protection of hippocampal neurogenesis in APP/PS1 mice treated with PREGS was accompanied with an improvement of spatial learning and memory.
Conclusion
The present study provides in vivo evidence that the treatment with either PREGS or DHEA could rescue the impaired neurite of newborn neurons, but only PREGS perfectly protected the survival and maturation of newly generated neuronal cells in APP/PS1 mice. The protection of PREGS against Aβ-impaired neurogenesis had a definite effect on improving cognitive deterioration in APP/PS1 mice.
引文
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