p75~(NTR)在Alzheimer病海马神经发生中作用机制的实验研究
摘要
研究背景
人口老龄化是当今世界各国家已经或即将面临的严峻社会问题,在我国这一问题将会尤为突出。截至去年底我国60岁以上的人口已达1.44亿,占总人口的11%,已进入老龄化社会。而在未来的几十年中,我国社会老龄化的推进速度将是十分迅速:预计到2014年,我国老年人口总数将突破2亿人,2026年超过3亿人,2050年将会达到近4.5亿人,占总人口的比例超过30%。随着人口的老龄化,老年痴呆的发病率日益升高。阿尔茨海默病(Alzheimer's disease,AD)是老年痴呆最常见类型,我国60岁以上人群的AD年发病率为0.42%-0.95%。AD是一种中枢神经系统退行性疾病,其突出临床特征是早期出现认知功能损害并进行性加重,逐渐会引起老年人生活能力丧失并在发病后7-10年导致其死亡,给社会经济发展和家庭带来沉重的负担。
近10余年来大量病理学、遗传学和转基因动物等方面的证据表明,Aβ是引起AD的主要致病物质。由Aβ所构成的细胞外SP的沉积(老年斑,senile plaque)及细胞内NFT(neurofibrillary tangle)是AD确诊的金标准。在AD未出现临床症状之前脑内即有可溶性Aβ纤维单体形成,并逐渐聚集形成老年斑,引起一系列复杂的病理生理变化。海马在学习记忆机制中,特别是空间学习记忆发挥重要作用,是AD最易受累脑区。成年哺乳动物海马齿状回颗粒细胞下层(subergranular zone,SGZ)神经发生终生存在,与学习记忆密切相关。局部环境因素影响其神经发生。在AD早期的病理阶段脑内产生的Aβ对海马神经发生有何影响、机制如何,是近年来神经科学领域研究的热点。阐明AD早期病理阶段海马神经发生的变化及其机制,对于AD的预防和治疗十分重要。
神经营养素(neurotrophin,NT)低亲和力的75000 NT受体(75 KD NT recep tor,p75~(NTR)),属1型跨膜TNF受体超家族。p75~(NTR)在Trk存在时被活化,提高对神经营养因子的反应性。Trk受体和p75~(NTR)协同作用,参与神经系统发育。近年来研究表明,p75~(NTR)在神经发育过程中调控神经细胞存活和死亡方面发挥关键作用,同时p75~(NTR)作为Aβ受体,介导了Aβ诱导的神经元死亡。p75~(NTR)是否参与Aβ对AD脑内神经发生的影响,目前存在较大争论。
为此,本研究构建了p75~(NTR)敲除AD小鼠模型,并通过p75~(NTR)胞外段(p75~(NTR-ECD))阻断在体海马干细胞和离体培养干细胞的p75~(NTR)激活,观察了海马NSCs神经发生的变化,从在体和离体水平探讨p75~(NTR)在AD海马神经发生中的作用。
方法
1.实验动物模型的制作及鉴定
通过APPswe/PS1dE9转基因AD(APP_(swe)~(+/-))小鼠和p75~(NTR)基因敲除(p75~(NTR-/-))小鼠(均源于美国Jackson实验室),将p75~(NTR-/-)小鼠和APPswe转基因AD小鼠杂交,产生出APPswep75~(NTR+/-)小鼠,然后反复与p75~(NTR-/-)杂交10代,得到具有99.9%以上129/Sv背景的杂合型APPswep75~(NTR-/-)小鼠;随后将APPswep75~(NTR-/-)小鼠与p75~(NTR+/+)小鼠(背景均为129/Sv)进行杂交,得到APPswep75~(NTR+/-)小鼠;将APP_(Swe)p75~(NTR+/-)小鼠分别和p75~(NTR-/-)以及p75~(NTR+/+)小鼠杂交,最终得到了具有近100%129/Sv背景的携带不同p75~(NTR)基因型的包括部分含有APPswe转基因的小鼠,并对成功交配繁殖后的小鼠进行了基因型鉴定。
2.p75~(NTR)基因敲除对AD小鼠海马神经发生的影响
根据动物基因型的鉴定结果,选取3、6、9月龄p75敲除AD小鼠(APP_(swe)~(+/-)p75~(NTR-/-))、AD小鼠(APP_(swe)~(+/-)p75~(NTR+/+))及野生型小鼠(APP_(swe)~(-/-)p75~(NTR+/+))作为实验鼠共9组,每组10只。采用Morris水迷宫检测各组小鼠潜伏期、游泳速度及空间探索能力的差异,腹腔注射BrdU(剂量为100ug/Kg体重,2/日,共3天)后免疫组化检测各组小鼠海马神经干细胞的增殖情况,并用免疫荧光双标(Brdu+DCX、Brdu+GFAP)结合激光共聚焦显微镜观察海马神经干细胞增生后的初步分化。
3.AD小鼠p75~(NTR-ECD)海马注射后干细胞增殖的变化
p75~(NTR)胞外段(Extracellular domain of p75~(NTR),p75~(NTR-ECD))是p75~(NTR)与其配体(包括Aβ)的结合部位。选取9月龄APPswe PS1dE9 AD小鼠12只,随机分为实验组和对照组,每组各6只,采用克隆表达的人p75~(NTR-ECD)向AD小鼠海马注射来阻断p75~(NTR)配体激活路径,对照组注射人IgG,腹腔注射BrdU(方法同2)后免疫组化检测两组AD小鼠海马神经干细胞增殖的变化。
4.p75~(NTR-ECD)对Aβ_(1-42)2培养海马干细胞增殖的影响
分离培养了成年小鼠(2月龄)海马神经干细胞,观察离体条件下加入Aβ42寡聚体10um/l对成年小鼠海马神经干细胞增殖的影响,然后用不同浓度人p75~(NTR)胞外段(p75~(NTR-ECD))中和培养体系中的Aβ42,细胞计数测定神经干细胞的增殖变化。
结果
1.实验小鼠基因型鉴定结果及生长情况
本实验所选用交配的两种动物即APPswe/PS1dE9转基因AD小鼠和p75~(NTR)基因敲除小鼠的遗传背景分别为C57BL/6、129/sv,将上述两种小鼠进行杂交,成功交配繁殖后对所生小鼠的基因型进行了鉴定,选择APP_(swe)~(+/-)p75~(NTR-/-)为p75敲除AD小鼠,APP_(swe)~(+/-)p75~(NTR+/+)为AD小鼠,APP_(swe)~(-/-)p75~(NTR+/+)为野生型小鼠。各种基因型小鼠的存活率、体重、繁殖生育能力及日常行为与其他遗传背景小鼠比较无明显异常表现。
2.p75~(NTR)基因敲除后AD小鼠海马神经发生的变化
随着月龄增加,各基因型小鼠海马神经发生均呈下降趋势,但AD鼠神经发生较野生鼠下降更为明显,同时与同月龄鼠相比增殖细胞向胶质分化比例增加、向神经元分化的比例下降,组间差别显著。通过比较不同月龄阶段同p75~(NTR)基因型小鼠海马神经干细胞的增殖分化情况,结果表明AD小鼠在p75~(NTR)敲除的情况下3、6、9月龄海马神经干细胞的增殖较未敲除鼠均增加,在6、9月龄鼠表现尤为显著,但增殖细胞的分化组间无明显差异。水迷宫检测显示3、6、9月龄AD小鼠的学习记忆能力与同龄野生鼠无显著差异,p75~(NTR)基因敲除后可促进AD小鼠海马的神经发生,但行为学检测发现对此阶段AD小鼠的记忆功能无明显影响。
3.p75~(NTR-ECD)对AD小鼠海马干细胞增殖的影响
通过向AD小鼠海马注射人p75~(NTR-ECD)融合蛋白,观察其对海马细胞增殖的影响。结果显示注射人p75~(NTR-ECD)融合蛋白AD小鼠海马BrdU阳性标记细胞较注射等mol量人IgG的AD小鼠明显增加,组间差异显著。
4.p75~(NTR-ECD)对Aβ培养海马干细胞增殖中的影响
成功分离、培养了成年小鼠海马NSCs。原代培养4-5d后多数成熟细胞死亡,而表达nestin抗原的神经细胞克隆球在培养7-10d形成,进一步将神经球分离成单细胞传代培养后,仍可在无血清培养基中快速生成并保持未分化状态、而且依旧表达nestin抗原的细胞克隆球,贴壁后可向神经元或胶质分化。离体条件下Aβ1-42对海马NSCs的增殖有明显的抑制作用;而如果同时加入p75~(NTR-ECD)胞外段后则可以阻断Aβ1-42对小鼠海马NSCs增殖的抑制作用。
结论
1.成功构建p75~(NTR)基因基因敲除AD小鼠模型
2.p75~(NTR)对AD小鼠海马神经干细胞增殖起抑制作用,对其分化无显著影响。
3.p75~(NTR)介导了Aβ1-42对海马干细胞增殖的抑制效应。
Background
The aging of the population is one of the greatest challenges for the world in the twenty-first century. This problem in China is more serious in the coming dacades. China has become an aged society since 1999 ,and the aged population(＞60years old) has reached 144 million by the end of last year. According to calculation based on the current prevalence data, there will be 0.45 billion elder people in China by 2050 and the proportion of aged people will exceed 30% by estimation. Alzheimer's disease (AD) is a neurodegenerative disease characterized histopathologically by beta-amyloid (Aβ)-containing senile plaque, neurofibrillary tangle and loss of neuron in certain brain areas, and clinically by progressive dementia. It is the most common cause of senile dementia of later life. Currently the incidence rate of AD among old people over 65 is 0.42 %-0.95% in china and the number of AD patients is about 3-4 million in China. AD is a major cause of disability and death in the elderly and results in heavy burden for the families and the society.
Over the past 10 years , it has been demonstrated that Aβis the main pathogenic cause of AD by pathology, genetics and transgenic studies. The senile plaque(SP) mainly copmosed of Aβwhich is currently considered as the key factor in pathogenesis of AD. Aβbegins to accumulate and deposit in the brain long before the clinical symptoms onset of AD .Hippocampus plays an important role in learning and memory ,while hippocampus is the most vulnerable part of the brain affected by AD. The granule cells in the subergranular zone(SGZ) of dentate gyrus is one of the few areas in adult mammalian brain that neurogenesis exists all the life.Local environmental factors play important roles in neurogenesis. Neurogenesis in hippocampus has close relation with memory, and is affected by the local environmental factors.What the role of Aβgenerated in the early stages of AD brain on neurogenesis in hippocampus is unknown, which attracts a lot of attention in the field of neuroscience recent years. It is very important to clarify the neurogenesis changes in hippocampus in the early pathological stage of AD for the prevention and treatment ofAD.
p75~(NTR), the low affinity receptor of neurotrophins, together with Trk receptors, play critical roles in regulating the survival and death of nerve cells during the neuron development. Recently p75~(NTR) has identified as an Aβreceptor and it mediates neuronal death induced by Aβ. But whether p75~(NTR) is involved in neurogenesis in AD brain affected by Aβis not clear.
With regard to this purpose, we established a p75~(NTR)-knockout AD mouse model, and the extracellular domain of p75~(NTR) (p75~(NTR-ECD) ) was injected into AD mouse hippocampus and added to neural stem cells (NSCs) cultured with Aβ. Then proliferation of NSCs was observed in vivo and in vitro. By such means we explored the role of p75 NTR in AD hippocampal neurogenesis.
Methods
1. Generation of animal model and genotyping
APPswe/PS1dE9 and p75~(N32TR-/-) mice were crossed and their progeny were genotyped. An APPswe/PS1dE9/p75~(NTR+/-) mouse was repeatedly backcrossed with a p75~(NTR-/-) mouse for 10 generations to produce APPswe/PS1dE9/p75~(NTR-/-) mice with nearly pure 129/Sv homozygosity. An APPswe/PS1dE9/p75~(NTR-/-) mouse was crossed with a 129/Sv mouse to obtain a male APPswe/PS1dE9/p75~(NTR+/-) mouse, which was next crossed with female 129/Sv mice and p75~(NTR-/-) mice to breed different kinds of genotype animals for the next experiments. Mice were maintained on ad libitum food and water with a 12-hour light/dark cycle.
2. Effect of p75~(NTR)on neurogenesis of hippocampus in AD mice
p75 knockout AD mice、AD mice and wild-type mice at age of 3, 6, 9 months were selected for the experiment. Morris Water Maze was used to measure the cognitive function of the mice. Intraperitoneal injection of BrdU (dose 100ug/Kg weight, 2 / day, total of 3 days) and immunohistochemical detection of BrdU were used to observe the proliferation of hippocampal NSCs in different groups of mice.The initial differentiation of hippocampal NSCs was observed by double-labeling immunofluorescence (Brdu + DCXor Brdu + GFAP) and confocal laser scanning microscope .
3. NSCs proliferation in AD mice hippocampus after p75~(NTR-ECD) injection .
Extracellular domain of p75~(NTR)is the binding site of Aβ. Twelve APPswe PS1dE9 ADmice at the age of 9-month-old were randomly divided into experimental and control groups with 6 mice in each group. The human p75~(NTR-ECD) was injected into the AD mouse hippocampus to block the endogenous p75~(NTR) activation,while human IgG was used as control .Intraperitoneal injection of BrdU and immunohistochemistry were used to examine the proliferation of NSCs in hippocampus .
4. The effect of p75~(NTR-ECD) on Aβ1-42cultured NSCs from mouse hippocampus.
Adult (2 months old) hippocampal NSCs were isolated and cultured.Aβ42 was addedinto the cultured cells at a concentration of 10um/1 and NSCs proliferation changes was observed.Then p75~(NTR-ECD) with different concentrations were added into the NSCscultured with Aβ1-42 to examine the role of p75~(NTR) in NSCs proliferation changes induced by Aβ1-42.
Results
1. Generation of p75~(NTR) knocked out AD mouse model.
APPswe/PS1dE9 transgenic AD mice carry a C57BL/6 gene back ground, and p75 knockout mice (p75NTR/ExonⅢ-/- mice) has a 129 / sv background .The two kinds of animals were crossed according to the designed step in order to get the same 129/sv back ground. As a result,six genetic types including APP_(swe)~(+/-)p75~(NTR-/-)、APP_(swe)~(+/-)p75~(NTR+/+)、APP_(swe)~(-/-)p75~(NTR-/-)、APP_(swe)~(-/-)p75~(NTR+/-)、APP_(swe)~(-/-)p75~(NTR+/+)、APP_(swe)~(+/-)p75~(NTR+/-) were produced.The different genetype animals were in normal condition. APP_(swe)~(+/-)p75~(NTR-/-)、APP_(swe)~(+/-)p75~(NTR+/+) , APP_(swe)~(-/-)p75~(NTR+/+)were selected as p75 konock-out AD mice, AD mice and wild mice.
2. Neurogenesis changes in AD hippocampus and the role of p75~(NTR)
The neurogenesis of hippocampus decreased with age increased in each genotype,with more drop in AD brain. The results of double labeling showed that the proportion of NSCs differentiation in p75~(NTR) knockout AD and AD mice was much different from wild mice-the proportion of BrdU+DCX was lower,and the proportion of BrdU+GFAP was higher than wild mice especially at 6、9 months of age (p＜0.05). There were no significant differences between each groups at 3 months of age. The results of Morris Water Maze test showed that there were no significant differences between AD mice , p75~(NTR) knockout mice and wild mice in the ability of learning and memory.
3. NSCs proliferation changes in AD mice hippocampus after p75~(NTR-ECD) injection
BrdU-positive cells in AD mouse hippocampus significantly increased afterp75~(NTR-ECD) hippcampus injection compared with control (p＜0.01).
4. The effect of p75~(NTR-ECD) on mouse hippocampal NSCs cultured with Aβ.
In vitro study we demonstrated that Aβ1-42 inhibited the proliferation of hippocampal NSCs, and p75~(NTR-ECD) blocked the inhibition effect of Aβ1-42 on the proliferation of hippocampal NSCs.
Conclusions
1. p75~(NTR) knockout AD mice were successfully constructed .
2. p75~(NTR) plays an inhibitory role in the proliferation of hippocampus NSCs in AD mice.
3. The inhibition of proliferation induced by Aβ_(1-42) is mediated by p75~(NTR).
人口老龄化是当今世界各国家已经或即将面临的严峻社会问题,在我国这一问题将会尤为突出。截至去年底我国60岁以上的人口已达1.44亿,占总人口的11%,已进入老龄化社会。而在未来的几十年中,我国社会老龄化的推进速度将是十分迅速:预计到2014年,我国老年人口总数将突破2亿人,2026年超过3亿人,2050年将会达到近4.5亿人,占总人口的比例超过30%。随着人口的老龄化,老年痴呆的发病率日益升高。阿尔茨海默病(Alzheimer's disease,AD)是老年痴呆最常见类型,我国60岁以上人群的AD年发病率为0.42%-0.95%。AD是一种中枢神经系统退行性疾病,其突出临床特征是早期出现认知功能损害并进行性加重,逐渐会引起老年人生活能力丧失并在发病后7-10年导致其死亡,给社会经济发展和家庭带来沉重的负担。
近10余年来大量病理学、遗传学和转基因动物等方面的证据表明,Aβ是引起AD的主要致病物质。由Aβ所构成的细胞外SP的沉积(老年斑,senile plaque)及细胞内NFT(neurofibrillary tangle)是AD确诊的金标准。在AD未出现临床症状之前脑内即有可溶性Aβ纤维单体形成,并逐渐聚集形成老年斑,引起一系列复杂的病理生理变化。海马在学习记忆机制中,特别是空间学习记忆发挥重要作用,是AD最易受累脑区。成年哺乳动物海马齿状回颗粒细胞下层(subergranular zone,SGZ)神经发生终生存在,与学习记忆密切相关。局部环境因素影响其神经发生。在AD早期的病理阶段脑内产生的Aβ对海马神经发生有何影响、机制如何,是近年来神经科学领域研究的热点。阐明AD早期病理阶段海马神经发生的变化及其机制,对于AD的预防和治疗十分重要。
神经营养素(neurotrophin,NT)低亲和力的75000 NT受体(75 KD NT recep tor,p75~(NTR)),属1型跨膜TNF受体超家族。p75~(NTR)在Trk存在时被活化,提高对神经营养因子的反应性。Trk受体和p75~(NTR)协同作用,参与神经系统发育。近年来研究表明,p75~(NTR)在神经发育过程中调控神经细胞存活和死亡方面发挥关键作用,同时p75~(NTR)作为Aβ受体,介导了Aβ诱导的神经元死亡。p75~(NTR)是否参与Aβ对AD脑内神经发生的影响,目前存在较大争论。
为此,本研究构建了p75~(NTR)敲除AD小鼠模型,并通过p75~(NTR)胞外段(p75~(NTR-ECD))阻断在体海马干细胞和离体培养干细胞的p75~(NTR)激活,观察了海马NSCs神经发生的变化,从在体和离体水平探讨p75~(NTR)在AD海马神经发生中的作用。
方法
1.实验动物模型的制作及鉴定
通过APPswe/PS1dE9转基因AD(APP_(swe)~(+/-))小鼠和p75~(NTR)基因敲除(p75~(NTR-/-))小鼠(均源于美国Jackson实验室),将p75~(NTR-/-)小鼠和APPswe转基因AD小鼠杂交,产生出APPswep75~(NTR+/-)小鼠,然后反复与p75~(NTR-/-)杂交10代,得到具有99.9%以上129/Sv背景的杂合型APPswep75~(NTR-/-)小鼠;随后将APPswep75~(NTR-/-)小鼠与p75~(NTR+/+)小鼠(背景均为129/Sv)进行杂交,得到APPswep75~(NTR+/-)小鼠;将APP_(Swe)p75~(NTR+/-)小鼠分别和p75~(NTR-/-)以及p75~(NTR+/+)小鼠杂交,最终得到了具有近100%129/Sv背景的携带不同p75~(NTR)基因型的包括部分含有APPswe转基因的小鼠,并对成功交配繁殖后的小鼠进行了基因型鉴定。
2.p75~(NTR)基因敲除对AD小鼠海马神经发生的影响
根据动物基因型的鉴定结果,选取3、6、9月龄p75敲除AD小鼠(APP_(swe)~(+/-)p75~(NTR-/-))、AD小鼠(APP_(swe)~(+/-)p75~(NTR+/+))及野生型小鼠(APP_(swe)~(-/-)p75~(NTR+/+))作为实验鼠共9组,每组10只。采用Morris水迷宫检测各组小鼠潜伏期、游泳速度及空间探索能力的差异,腹腔注射BrdU(剂量为100ug/Kg体重,2/日,共3天)后免疫组化检测各组小鼠海马神经干细胞的增殖情况,并用免疫荧光双标(Brdu+DCX、Brdu+GFAP)结合激光共聚焦显微镜观察海马神经干细胞增生后的初步分化。
3.AD小鼠p75~(NTR-ECD)海马注射后干细胞增殖的变化
p75~(NTR)胞外段(Extracellular domain of p75~(NTR),p75~(NTR-ECD))是p75~(NTR)与其配体(包括Aβ)的结合部位。选取9月龄APPswe PS1dE9 AD小鼠12只,随机分为实验组和对照组,每组各6只,采用克隆表达的人p75~(NTR-ECD)向AD小鼠海马注射来阻断p75~(NTR)配体激活路径,对照组注射人IgG,腹腔注射BrdU(方法同2)后免疫组化检测两组AD小鼠海马神经干细胞增殖的变化。
4.p75~(NTR-ECD)对Aβ_(1-42)2培养海马干细胞增殖的影响
分离培养了成年小鼠(2月龄)海马神经干细胞,观察离体条件下加入Aβ42寡聚体10um/l对成年小鼠海马神经干细胞增殖的影响,然后用不同浓度人p75~(NTR)胞外段(p75~(NTR-ECD))中和培养体系中的Aβ42,细胞计数测定神经干细胞的增殖变化。
结果
1.实验小鼠基因型鉴定结果及生长情况
本实验所选用交配的两种动物即APPswe/PS1dE9转基因AD小鼠和p75~(NTR)基因敲除小鼠的遗传背景分别为C57BL/6、129/sv,将上述两种小鼠进行杂交,成功交配繁殖后对所生小鼠的基因型进行了鉴定,选择APP_(swe)~(+/-)p75~(NTR-/-)为p75敲除AD小鼠,APP_(swe)~(+/-)p75~(NTR+/+)为AD小鼠,APP_(swe)~(-/-)p75~(NTR+/+)为野生型小鼠。各种基因型小鼠的存活率、体重、繁殖生育能力及日常行为与其他遗传背景小鼠比较无明显异常表现。
2.p75~(NTR)基因敲除后AD小鼠海马神经发生的变化
随着月龄增加,各基因型小鼠海马神经发生均呈下降趋势,但AD鼠神经发生较野生鼠下降更为明显,同时与同月龄鼠相比增殖细胞向胶质分化比例增加、向神经元分化的比例下降,组间差别显著。通过比较不同月龄阶段同p75~(NTR)基因型小鼠海马神经干细胞的增殖分化情况,结果表明AD小鼠在p75~(NTR)敲除的情况下3、6、9月龄海马神经干细胞的增殖较未敲除鼠均增加,在6、9月龄鼠表现尤为显著,但增殖细胞的分化组间无明显差异。水迷宫检测显示3、6、9月龄AD小鼠的学习记忆能力与同龄野生鼠无显著差异,p75~(NTR)基因敲除后可促进AD小鼠海马的神经发生,但行为学检测发现对此阶段AD小鼠的记忆功能无明显影响。
3.p75~(NTR-ECD)对AD小鼠海马干细胞增殖的影响
通过向AD小鼠海马注射人p75~(NTR-ECD)融合蛋白,观察其对海马细胞增殖的影响。结果显示注射人p75~(NTR-ECD)融合蛋白AD小鼠海马BrdU阳性标记细胞较注射等mol量人IgG的AD小鼠明显增加,组间差异显著。
4.p75~(NTR-ECD)对Aβ培养海马干细胞增殖中的影响
成功分离、培养了成年小鼠海马NSCs。原代培养4-5d后多数成熟细胞死亡,而表达nestin抗原的神经细胞克隆球在培养7-10d形成,进一步将神经球分离成单细胞传代培养后,仍可在无血清培养基中快速生成并保持未分化状态、而且依旧表达nestin抗原的细胞克隆球,贴壁后可向神经元或胶质分化。离体条件下Aβ1-42对海马NSCs的增殖有明显的抑制作用;而如果同时加入p75~(NTR-ECD)胞外段后则可以阻断Aβ1-42对小鼠海马NSCs增殖的抑制作用。
结论
1.成功构建p75~(NTR)基因基因敲除AD小鼠模型
2.p75~(NTR)对AD小鼠海马神经干细胞增殖起抑制作用,对其分化无显著影响。
3.p75~(NTR)介导了Aβ1-42对海马干细胞增殖的抑制效应。
Background
The aging of the population is one of the greatest challenges for the world in the twenty-first century. This problem in China is more serious in the coming dacades. China has become an aged society since 1999 ,and the aged population(＞60years old) has reached 144 million by the end of last year. According to calculation based on the current prevalence data, there will be 0.45 billion elder people in China by 2050 and the proportion of aged people will exceed 30% by estimation. Alzheimer's disease (AD) is a neurodegenerative disease characterized histopathologically by beta-amyloid (Aβ)-containing senile plaque, neurofibrillary tangle and loss of neuron in certain brain areas, and clinically by progressive dementia. It is the most common cause of senile dementia of later life. Currently the incidence rate of AD among old people over 65 is 0.42 %-0.95% in china and the number of AD patients is about 3-4 million in China. AD is a major cause of disability and death in the elderly and results in heavy burden for the families and the society.
Over the past 10 years , it has been demonstrated that Aβis the main pathogenic cause of AD by pathology, genetics and transgenic studies. The senile plaque(SP) mainly copmosed of Aβwhich is currently considered as the key factor in pathogenesis of AD. Aβbegins to accumulate and deposit in the brain long before the clinical symptoms onset of AD .Hippocampus plays an important role in learning and memory ,while hippocampus is the most vulnerable part of the brain affected by AD. The granule cells in the subergranular zone(SGZ) of dentate gyrus is one of the few areas in adult mammalian brain that neurogenesis exists all the life.Local environmental factors play important roles in neurogenesis. Neurogenesis in hippocampus has close relation with memory, and is affected by the local environmental factors.What the role of Aβgenerated in the early stages of AD brain on neurogenesis in hippocampus is unknown, which attracts a lot of attention in the field of neuroscience recent years. It is very important to clarify the neurogenesis changes in hippocampus in the early pathological stage of AD for the prevention and treatment ofAD.
p75~(NTR), the low affinity receptor of neurotrophins, together with Trk receptors, play critical roles in regulating the survival and death of nerve cells during the neuron development. Recently p75~(NTR) has identified as an Aβreceptor and it mediates neuronal death induced by Aβ. But whether p75~(NTR) is involved in neurogenesis in AD brain affected by Aβis not clear.
With regard to this purpose, we established a p75~(NTR)-knockout AD mouse model, and the extracellular domain of p75~(NTR) (p75~(NTR-ECD) ) was injected into AD mouse hippocampus and added to neural stem cells (NSCs) cultured with Aβ. Then proliferation of NSCs was observed in vivo and in vitro. By such means we explored the role of p75 NTR in AD hippocampal neurogenesis.
Methods
1. Generation of animal model and genotyping
APPswe/PS1dE9 and p75~(N32TR-/-) mice were crossed and their progeny were genotyped. An APPswe/PS1dE9/p75~(NTR+/-) mouse was repeatedly backcrossed with a p75~(NTR-/-) mouse for 10 generations to produce APPswe/PS1dE9/p75~(NTR-/-) mice with nearly pure 129/Sv homozygosity. An APPswe/PS1dE9/p75~(NTR-/-) mouse was crossed with a 129/Sv mouse to obtain a male APPswe/PS1dE9/p75~(NTR+/-) mouse, which was next crossed with female 129/Sv mice and p75~(NTR-/-) mice to breed different kinds of genotype animals for the next experiments. Mice were maintained on ad libitum food and water with a 12-hour light/dark cycle.
2. Effect of p75~(NTR)on neurogenesis of hippocampus in AD mice
p75 knockout AD mice、AD mice and wild-type mice at age of 3, 6, 9 months were selected for the experiment. Morris Water Maze was used to measure the cognitive function of the mice. Intraperitoneal injection of BrdU (dose 100ug/Kg weight, 2 / day, total of 3 days) and immunohistochemical detection of BrdU were used to observe the proliferation of hippocampal NSCs in different groups of mice.The initial differentiation of hippocampal NSCs was observed by double-labeling immunofluorescence (Brdu + DCXor Brdu + GFAP) and confocal laser scanning microscope .
3. NSCs proliferation in AD mice hippocampus after p75~(NTR-ECD) injection .
Extracellular domain of p75~(NTR)is the binding site of Aβ. Twelve APPswe PS1dE9 ADmice at the age of 9-month-old were randomly divided into experimental and control groups with 6 mice in each group. The human p75~(NTR-ECD) was injected into the AD mouse hippocampus to block the endogenous p75~(NTR) activation,while human IgG was used as control .Intraperitoneal injection of BrdU and immunohistochemistry were used to examine the proliferation of NSCs in hippocampus .
4. The effect of p75~(NTR-ECD) on Aβ1-42cultured NSCs from mouse hippocampus.
Adult (2 months old) hippocampal NSCs were isolated and cultured.Aβ42 was addedinto the cultured cells at a concentration of 10um/1 and NSCs proliferation changes was observed.Then p75~(NTR-ECD) with different concentrations were added into the NSCscultured with Aβ1-42 to examine the role of p75~(NTR) in NSCs proliferation changes induced by Aβ1-42.
Results
1. Generation of p75~(NTR) knocked out AD mouse model.
APPswe/PS1dE9 transgenic AD mice carry a C57BL/6 gene back ground, and p75 knockout mice (p75NTR/ExonⅢ-/- mice) has a 129 / sv background .The two kinds of animals were crossed according to the designed step in order to get the same 129/sv back ground. As a result,six genetic types including APP_(swe)~(+/-)p75~(NTR-/-)、APP_(swe)~(+/-)p75~(NTR+/+)、APP_(swe)~(-/-)p75~(NTR-/-)、APP_(swe)~(-/-)p75~(NTR+/-)、APP_(swe)~(-/-)p75~(NTR+/+)、APP_(swe)~(+/-)p75~(NTR+/-) were produced.The different genetype animals were in normal condition. APP_(swe)~(+/-)p75~(NTR-/-)、APP_(swe)~(+/-)p75~(NTR+/+) , APP_(swe)~(-/-)p75~(NTR+/+)were selected as p75 konock-out AD mice, AD mice and wild mice.
2. Neurogenesis changes in AD hippocampus and the role of p75~(NTR)
The neurogenesis of hippocampus decreased with age increased in each genotype,with more drop in AD brain. The results of double labeling showed that the proportion of NSCs differentiation in p75~(NTR) knockout AD and AD mice was much different from wild mice-the proportion of BrdU+DCX was lower,and the proportion of BrdU+GFAP was higher than wild mice especially at 6、9 months of age (p＜0.05). There were no significant differences between each groups at 3 months of age. The results of Morris Water Maze test showed that there were no significant differences between AD mice , p75~(NTR) knockout mice and wild mice in the ability of learning and memory.
3. NSCs proliferation changes in AD mice hippocampus after p75~(NTR-ECD) injection
BrdU-positive cells in AD mouse hippocampus significantly increased afterp75~(NTR-ECD) hippcampus injection compared with control (p＜0.01).
4. The effect of p75~(NTR-ECD) on mouse hippocampal NSCs cultured with Aβ.
In vitro study we demonstrated that Aβ1-42 inhibited the proliferation of hippocampal NSCs, and p75~(NTR-ECD) blocked the inhibition effect of Aβ1-42 on the proliferation of hippocampal NSCs.
Conclusions
1. p75~(NTR) knockout AD mice were successfully constructed .
2. p75~(NTR) plays an inhibitory role in the proliferation of hippocampus NSCs in AD mice.
3. The inhibition of proliferation induced by Aβ_(1-42) is mediated by p75~(NTR).
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