proBDNF对老龄鼠认知功能的影响及机制研究
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摘要
研究背景
阿尔茨海默病(Alzheimer's disease,AD)是老年人群痴呆的主要类型,已经成为危害老年人群健康和生命的重要疾病。目前全球有AD患者约1200万人,随着人口老龄化问题的加剧,预计到2050年全球将共有AD患者4500万。AD的患者给家庭和社会带来了严重的经济负担。
我国人口老龄化问题尤为严峻。我国已于1999年进入老龄社会,是较早进入老龄社会的发展中国家之一,也是世界上老年人口最多的国家。21世纪的中国将是一个不可逆转的老龄社会。按目前AD的发病率推算,到2050年我国将有AD患者800万-1200万。AD将成为我国的一个严峻的经济和社会负担,对AD的防治非常紧迫。
AD海马的病理变化之一是海马神经元的缺失,研究如何防止神经元丢失以及补充缺失的神经元成为神经科学领域的研究热点。近年研究发现,哺乳动物海马齿状回颗粒层下区终生存在着神经发生的能力,但成年动物这种自发的神经发生是有限的,而且随着年龄增长逐渐下降,海马神经发生的下降与老年认知功能损害相关。因此,研究如何促进老龄海马神经元的增殖、存活及功能联系有望为AD的防治提供新的策略。
脑源性神经营养因子(Brain-derived neurothrophic factor,BDNF)通过促进细胞的增殖、分化和存活而影响神经元的神经发生,BDNF还与活动依赖性突触可塑性有关,对改善认知功能有重要作用。BDNF由其前体物质脑源性神经营养因子前体(precursorof brain derived neurotrophic factor,proBDNF)在胞外裂解而成。最近研究表明,proBDNF是BDNF基因表达产物在胞外的主要存在形式之一,proBDNF与BDNF共同广泛存在于中枢神经系统,包括海马;未裂解的proBDNF本身可能有着与BDNF作用相反的功能;proBDNF第66个氨基酸位点发生变异后,BDNF分泌受限,海马的功能受到抑制,学习记忆能力下降;病理情况下,如AD,P75~(NTR)表达升高,proBDNF与之结合后能够促进海马长时程抑制;老年以及AD早期动物的脑内BDNFmRNA表达增加,proBDNF蛋白含量增加。这些研究结果提示,proBDNF在认知功能障碍发生、发展过程中可能有着重要作用。
进一步认识proBDNF在老龄海马神经发生以及突触可塑性中的作用,对于AD的预防有重要意义。为此,本实验的主要内容包括:基因重组抗裂解proBDNF蛋白的表达、纯化、鉴定及生物学活性测定;探讨proBDNF对老龄鼠认知功能的影响;通过体内外实验从海马神经发生及突触可塑性变化角度探讨proBDNF对老龄鼠认知功能影响的机制。
方法
1.基因重组proBDNF蛋白在大肠杆菌中的表达及活性鉴定
以大鼠点突变型基因的全长proBDNF cDNA为模板,用PCR方法扩增proBDNF的cDNA,应用基因重组技术将大鼠proBDNF cDNA克隆到质粒pET-28a中,进行限制性内切酶酶切分析和DNA测序鉴定。将重组质粒转化大肠杆菌BL21,经IPTG诱导表达后,用Ni-NTA亲和层析纯化获取蛋白,用SDS-PAGE和western blot方法鉴别,DAPI法检测重组蛋白对PC12细胞凋亡的影响。
2.proBDNF对老龄鼠认知功能影响
实验动物采用18月龄C57BL/6J鼠,随机分为三组:proBDNF组、抗proBDNF组和对照组,每组10只,分别采用微量渗透泵连续6天向右侧海马注射proBDNF、羊抗proBDNF或BSA,浓度均为1μg/μl,速度0.2μl/h。术后21天,采用Morris水迷宫进行航行定位实验测定老龄鼠的平均逃避潜伏期、游泳速度,并进行空间探索实验测定动物在月台所在象限时间的百分比。
3.proBDNF对老龄鼠海马神经发生的影响
实验动物采用18月龄C57BL/6J鼠,随机分为三组:proBDNF组,抗proBDNF组及对照组,每组10只,分别采用微量渗透泵连续6天向右侧海马注射BSA、proBDNF或羊抗proBDNF,浓度均为1μg/μl,速度0.2μl/h。动物术后当日始给予BrdU50mg/kg.体重,腹腔注射,每日2次,持续6天。分别于术后7天、28天检测海马细胞增殖情况,并利用免疫荧光三标法对Brdu阳性细胞进行鉴定;
4.proBDNF对老龄鼠海马突触可塑性的影响
实验动物采用18月龄C57BL/6J鼠,随机分为三组:proBDNF组,抗proBDNF组及对照组,每组5只,分别采用微量渗透泵连续6天向右侧海马注射BSA、proBDNF或羊抗proBDNF,浓度均为1μg/μl,速度0.2μl/h。术后28天使用免疫印迹分析方法检测海马synapsinⅠ和pCREB的变化。
5.proBDNF对培养的海马神经元增殖和凋亡的影响
采用出生24小时的雌性P75~(NTR)基因敲除鼠以及野生型鼠海马建立海马神经元原代培养,分别采用含proBDNF(10ng/ml),proBDNF(10ng/ml)+sortilin-FC(20ng/ml),或BSA(10ng/ml)的细胞培养液进行培养,采用BrdU标记法观察海马神经元增殖情况,用TUNEL法检测凋亡细胞。
结果
1.基因重组proBDNF蛋白在大肠杆菌中的表达及活性鉴定
扩增出的大鼠proBDNF cDNA片段克隆进了原核表达载体,经酶切和核酸测序鉴定,得到了正确的重组质粒pET-proBDNF,并在大肠杆菌中获得了表达。纯化后的蛋白经考马氏亮蓝染色呈单一条带,用抗proBDNF的抗体进行western blot分析证明目的蛋白获得了表达。免疫组化结果提示,基因重组proBDNF蛋白能够促进PC12细胞凋亡,而亲合纯化的羊抗proBDNF抗体能够中和proBDNF的促细胞凋亡作用。
2.proBDNF对老龄鼠认知功能影响
Morris水迷宫测试实验结果显示,从Morris水迷宫实验第3天起,proBDNF注射组平均逃避潜伏期明显长于对照组;而抗proBDNF组平均逃避潜伏期比对照组短。各组之间游泳速度相差不显著。在空间探索实验中,proBDNF组在平台所在象限游泳时间的百分比明显比对照组小,动物入水后无目的游动,而抗proBDNF组在平台所在象限游泳时间的百分比明显比对照组增加,其运动轨迹主要集中于原平台所在位置。
3.proBDNF对老龄鼠海马神经发生的影响
免疫组化结果显示,术后第7天,典型的BrdU阳性细胞内有深棕黄色的颗粒,这些阳性细胞大部分位于颗粒细胞层与门区之间,即所谓的下颗粒区,往往紧密排列、成簇出现,细胞形状不规则。术后第28天,BrdU阳性细胞呈椭圆型或圆形,形态接近颗粒细胞,多数位于颗粒细胞层,也有零星细胞位于海马门区。
术后第7天及第28天proBDNF组每张切片BrdU阳性细胞数均分别明显低于BSA对照组(p＜0.01),而抗proBDNF组则明显高于BSA对照组(p＜0.01)。术后第28天,proBDNF组、抗proBDNF组及对照组,各组中BrdU阳性细胞数与术后第7天同组比较均明显下降(其中proBDNF组下降最明显),分别为术后第7天的50%、38%和60%。
免疫荧光三标法对术后第7天和第28天BrdU阳性细胞进行鉴定,结果发现proBDNF组、抗proBDNF组以及BSA组,三组中各细胞类型的百分比无显著性差异。
4.proBDNF对老龄鼠海马突触可塑性的影响
术后第28天免疫印迹结果显示,proBDNF组海马synapsinⅠ以及pCREB的含量分别较BSA对照组明显减少(p＜0.01),而抗proBDNF组海马synapsinⅠ以及pCREB的含量则明显增加(p＜0.01)。
5.proBDNF对培养的海马神经元增殖和凋亡的影响
对于野生型鼠培养海马神经元,与对照组比较,proBDNF组BrdU阳性细胞百分比明显降低(p＜0.01)、TUNEL阳性细胞百分比明显增加(p＜0.01),而proBDNF+sortilin-FC组BrdU阳性细胞百分比、TUNEL阳性细胞百分比与对照组比较无显著差异。
P75~(NTR)基因敲除鼠培养神经元中,proBDNF组BrdU阳性细胞百分比、TUNEL阳性细胞百分比与对照组比较无显著差异。
结论
1.本研究成功构建了表达基因重组大鼠proBDNF的原核表达载体,基因重组大鼠proBDNF蛋白在大肠杆菌中获得了表达和纯化,所获得的基因重组蛋白具有较好的生物学活性。
2.通过Morris水迷宫实验,证实proBDNF能够降低老龄鼠的学习记忆功能,而阻断内源性proBDNF后能改善老龄鼠的学习记忆能力。
3.proBDNF可抑制海马细胞增殖、降低新生细胞的存活率,但对细胞分化无影响。
4.proBDNF可降低海马synapsinⅠ和pCREB蛋白的含量,提示proBDNF可降低老龄鼠突触可塑性。
5.proBDNF抑制体外培养的海马神经元的增殖、促进细胞凋亡,proBDNF这种作用需要P75~(NTR)及sortilin的参与。
6.proBDNF可能通过抑制老龄鼠海马的神经发生、降低海马突触可塑性,从而降低老龄鼠的学习记忆功能。
Background
Alzheimer'disease(AD) is the most common form of dementia in later life,and a major cause of disability and death in the elderly.Currently there are more than 12 million individuals affected with AD worldwide,and it is projected that the prevalence will nearly quadruple in the next 50 years,by which time approximately 45 million will be afflicted with the disease.It is a huge burden for the families and the society.
China has been facing a very serious and irreversible situation of population aging during 21st century.Since 1999 China's population has become aged with the most amount of old people in the world.According to calculation based on the current prevalence data,it is estimated that there will be 8 to 12 million AD patients in China by 2050.
Alzheimer's disease is associated with the loss of neurons in areas of the brain that are vital to memory and other mental abilities,like the hippocampus.In elderly humans, imaging studies have shown hippocampal atrophy.It is of great importance and interest to develop effective approaches which are able to prevent the incidence of neuron loss. Neurogenesis in adult mammals occurs in several regions,including the forebrain subventricular zone(SVZ) and the dentate gyrus of the hippocampal formation. Hippocampal neurogenesis occurs throughout the adulthood and is important for learning and memory,but it declines with age.Reduced neurogenesis in the aged hippocampus has been shown to be associated with cognitive deficits.Neurogenesis maybe a potential therapeutic strategy for AD.
Brain-derived neurothrophic factor(BDNF) can promote the proliferation, differentiation and survival of neuron.BDNF can enhance the activity-dependent synaptic plasticity.It is recently confirmed that the precursor of BDNF(proBDNF) is the main expressing product of BDNFmRNA outside the cell.proBDNF distributes widely in the adult animal,especially in the central nervous system.The uncleaved precursor may play a different role from that of mature BDNF.It has been shown that a single amino acid mutation(Val66Met) in the proregion of BDNF affects the sorting of the molecule into the nerve terminals,retards activity-dependent secretion and reduces learning functions of the hippocampus.Under pathological conditions,such as aging and early stage of AD,the proBDNF and P75~(NTR) expression are upregulated.All of these indicate that proBDNF is not merely precursor of BDNF and may have important roles in the development of cognition impairment.
It is important for the prevention of AD to study the roles of proBDNF in hippocampal neurogenesis and synaptic plasticity.Thus in the present study,there are main contents including expression,purification of cleave -resistant recombinant proBDNF protein,and study on its functional characterization.Effects of proBDNF on the cognition function in aged mice were observed.By in vivo and in vitro study,we evaluated the effects of proBDNF on hippocampal neurogenesis and synaptic plasticity,and investigated the mechanism of the effects of proBDNF on cognition function.
Method
1.Expression,purification of recombinant proBDNF protein in E.coli.and its functional characterization
The cDNA fragment from proBDNF was obtained by standard PCR method with a full-length rat mutated proBDNF cDNA as template,and was inserted into plasmid pET-28a by means of gene rearrangement.The recombinant plasmid pET-proBDNF was identified by restriction endonuclease analysis and DNA sequencing.The cloned pET-proBDNF plasmid was transformed into E.coli host strain,BL21.Following induction by IPTG,the recombinant protein was expressed and then purified by Ni-NAT affinity chromatography under denaturing conditions.The interest protein was viewed by SDS-PAGE,further characterized by western blot.The apoptosis of PC12 cells was evaluated by DAPI assay.
2.Effects of proBDNF on cognition function in aged mice
Thirty aged C57BL/6J mice(18months old)were randomly divided in to three groups: proBDNF group,anti-proBDNF group,or bovine serum albumin(BSA) group(n=10).A Alzet osmotic minipump was connected to right hippocampus of the mouse.Pumps were filled with proBDNF(1μg/μl),sheep antibody to proBDNF(1μg/μl),or BSA(1μg/μl), respectively.Mice received the injection for 6 days at the speed of 0.2μl/h.21days after surgery,the animals were subjected for Morris Water Maze to test mean escape latency, swimming speed and percentage of time spent in the target quardrant.
3.Effects of proBDNF on hippocampal neurogenesis in aged mice.
Thirty 18-month-old C57BL/6J mice were used in this experiment.Animals received proBDNF,sheep antibody to proBDNF or BSA as described previously in step 2.BrdU(50 mg/kg,i.p.) was injected twice per day for 6 days immediately after surgery.7days and 28 days postsurgery,immunohistochemistry was processed to examine the BrdU positive cells, and immunofluoresent triple labeling was processed to examine the phenotype of the newly generated cells.
4.Effects of proBDNF on hippocampal synaptic plasticity in aged mice.
Fifteen 18-month-old C57BL/6J mice were used in this experiment.Animals received proBDNF,sheep antibody to proBDNF or BSA as described previously in step 2.28 days postsurgery,western blot were used to observe changes of the synaptic plasticity marker-pCREB and synapsin I.
5.Effects of proBDNF on the proliferation and apoptosis of cultured hippocampal neuron.
The primary hippocampal cell cultures were prepared from 1-day-old female P75~(NTR) knocked out mice and their wild-type littermates.Cells were co-cultured with cleaved resistant proBDNF,proBDNF+sortilin-FC,or BSA,respectively.Proliferation was tested by immunohistochemstry on BrdU,and apoptosis of hippocampal neuron was detected by TUNEL assay.
Results
1.Expression,purification of recombinant proBDNF protein in E.coli.and its functional characterization
The rat proBDNF cDNA was amplified and cloned into prokaryotic expression vector. The restriction endonuclease analysis and DNA sequencing proved that the plasmid pET-proBDNF was obtained.The recombinant protein was expressed in E.coli system. After Coomassie brilliant blue staining,the recombinant protein showed an exclusive band; western blot analysis with anti-proBDNF antibody supported that the expressed protein was recombinant proBDNF.The recombinant rat proBDNF protein could enhance the apoptosis of PC12 cells.Affinity purified antibody to proBDNF could neutralize the effect of proBDNF
2.Effects of proBDNF on cognition function in aged mice
Compared with BSA control group,proBDNF group had longer mean escape latency (p＜0.05),while the mean escape latency in antiproBDNF group was shorter(p＜0.05).When it comes to swimming speed,there had no difference between each group.Compared with control group,mice in proBDNF group spent less time in the target quadrant,while mice in anti-proBDNF group spent more time in the target quadrant(p＜0.05).
3.Effects of proBDNF on hippocampal neurogenesis in aged mice.
7days and 28days postsurgery,proBDNF group had less BrdU positive cells in dentate gyrus(p＜0.01),while antiproBDNF had more BrdU positive cells(p＜0.01),compared with control group,respectively.After 28days postsurgery,the BrdU positive cells decreased in all the groups,but proBDNF decreased the most dramatically.Immunofluoresent triple labeling showed that there had not difference of phenotype of BrdU positive cells between each group.
4.Effects of proBDNF on hippocampal synaptic plasticity in aged mice.
28days postsurgery,western blot showed that synapsin I and P-CREB in hippocampus were lower in proBDNF group than that of control group(p＜0.01).But anti-proBDNF group had more synapsin I and pCREB,compared with control group(p＜0.01)
5.Effects of proBDNF on the proliferation and apoptosis of cultured hippocampal neuron.
The number of BrdU positive cells in wild type mice decreased significantly in proBDNF group(p＜0.01,compared with control group),but there had no difference between proBDNF+sortilin-Fc group and contral group.In P75~(NTR) knockout mice,the BrdU positive cells in proBDNF group was the same as the control group.
On the contrary,the number of TUNEL positive cells in wild type mice increased significantly in proBDNF group(p＜0.01,compared with control group),while there had no difference between proBDNF+sortilin-Fc group and control group.In P75~(NTR) knockout mice,both the control group and proBDNF group had the same percentage of TUNEL positive cell.
Conclusions
1.The prokaryotic expression vector for rat proBDNF is successfully constructed.The recombinant rat proBDNF protein can be expressed and purified in E.coli.and has a good biological activity.
2.proBDNF can suppress the learning and memory ability of aged mice.It indicates that proBDNF plays a different role from that of mature BDNF.
3.proBDNF suppressed the proliferation and survival of hippocampal neuron in dentate gyrus in aged mice.
4.proBDNF downregulated the expression of pCREB and synapsin I protein in hippocampus of aged mice.
5.proBDNF can inhibit the proliferation of neurons in dentate gyrus and initiate cell death.Interaction of proBDNF with both receptors of sortilin and P75~(NTR) on the cell surface is required for these effects.
6.proBDNF can suppress the learning and memory ability of aged mice by inhibiting the hippocampal neurogenesis and downregulating the expression of pCREB and synapsin I protein in hippocampus.
阿尔茨海默病(Alzheimer's disease,AD)是老年人群痴呆的主要类型,已经成为危害老年人群健康和生命的重要疾病。目前全球有AD患者约1200万人,随着人口老龄化问题的加剧,预计到2050年全球将共有AD患者4500万。AD的患者给家庭和社会带来了严重的经济负担。
我国人口老龄化问题尤为严峻。我国已于1999年进入老龄社会,是较早进入老龄社会的发展中国家之一,也是世界上老年人口最多的国家。21世纪的中国将是一个不可逆转的老龄社会。按目前AD的发病率推算,到2050年我国将有AD患者800万-1200万。AD将成为我国的一个严峻的经济和社会负担,对AD的防治非常紧迫。
AD海马的病理变化之一是海马神经元的缺失,研究如何防止神经元丢失以及补充缺失的神经元成为神经科学领域的研究热点。近年研究发现,哺乳动物海马齿状回颗粒层下区终生存在着神经发生的能力,但成年动物这种自发的神经发生是有限的,而且随着年龄增长逐渐下降,海马神经发生的下降与老年认知功能损害相关。因此,研究如何促进老龄海马神经元的增殖、存活及功能联系有望为AD的防治提供新的策略。
脑源性神经营养因子(Brain-derived neurothrophic factor,BDNF)通过促进细胞的增殖、分化和存活而影响神经元的神经发生,BDNF还与活动依赖性突触可塑性有关,对改善认知功能有重要作用。BDNF由其前体物质脑源性神经营养因子前体(precursorof brain derived neurotrophic factor,proBDNF)在胞外裂解而成。最近研究表明,proBDNF是BDNF基因表达产物在胞外的主要存在形式之一,proBDNF与BDNF共同广泛存在于中枢神经系统,包括海马;未裂解的proBDNF本身可能有着与BDNF作用相反的功能;proBDNF第66个氨基酸位点发生变异后,BDNF分泌受限,海马的功能受到抑制,学习记忆能力下降;病理情况下,如AD,P75~(NTR)表达升高,proBDNF与之结合后能够促进海马长时程抑制;老年以及AD早期动物的脑内BDNFmRNA表达增加,proBDNF蛋白含量增加。这些研究结果提示,proBDNF在认知功能障碍发生、发展过程中可能有着重要作用。
进一步认识proBDNF在老龄海马神经发生以及突触可塑性中的作用,对于AD的预防有重要意义。为此,本实验的主要内容包括:基因重组抗裂解proBDNF蛋白的表达、纯化、鉴定及生物学活性测定;探讨proBDNF对老龄鼠认知功能的影响;通过体内外实验从海马神经发生及突触可塑性变化角度探讨proBDNF对老龄鼠认知功能影响的机制。
方法
1.基因重组proBDNF蛋白在大肠杆菌中的表达及活性鉴定
以大鼠点突变型基因的全长proBDNF cDNA为模板,用PCR方法扩增proBDNF的cDNA,应用基因重组技术将大鼠proBDNF cDNA克隆到质粒pET-28a中,进行限制性内切酶酶切分析和DNA测序鉴定。将重组质粒转化大肠杆菌BL21,经IPTG诱导表达后,用Ni-NTA亲和层析纯化获取蛋白,用SDS-PAGE和western blot方法鉴别,DAPI法检测重组蛋白对PC12细胞凋亡的影响。
2.proBDNF对老龄鼠认知功能影响
实验动物采用18月龄C57BL/6J鼠,随机分为三组:proBDNF组、抗proBDNF组和对照组,每组10只,分别采用微量渗透泵连续6天向右侧海马注射proBDNF、羊抗proBDNF或BSA,浓度均为1μg/μl,速度0.2μl/h。术后21天,采用Morris水迷宫进行航行定位实验测定老龄鼠的平均逃避潜伏期、游泳速度,并进行空间探索实验测定动物在月台所在象限时间的百分比。
3.proBDNF对老龄鼠海马神经发生的影响
实验动物采用18月龄C57BL/6J鼠,随机分为三组:proBDNF组,抗proBDNF组及对照组,每组10只,分别采用微量渗透泵连续6天向右侧海马注射BSA、proBDNF或羊抗proBDNF,浓度均为1μg/μl,速度0.2μl/h。动物术后当日始给予BrdU50mg/kg.体重,腹腔注射,每日2次,持续6天。分别于术后7天、28天检测海马细胞增殖情况,并利用免疫荧光三标法对Brdu阳性细胞进行鉴定;
4.proBDNF对老龄鼠海马突触可塑性的影响
实验动物采用18月龄C57BL/6J鼠,随机分为三组:proBDNF组,抗proBDNF组及对照组,每组5只,分别采用微量渗透泵连续6天向右侧海马注射BSA、proBDNF或羊抗proBDNF,浓度均为1μg/μl,速度0.2μl/h。术后28天使用免疫印迹分析方法检测海马synapsinⅠ和pCREB的变化。
5.proBDNF对培养的海马神经元增殖和凋亡的影响
采用出生24小时的雌性P75~(NTR)基因敲除鼠以及野生型鼠海马建立海马神经元原代培养,分别采用含proBDNF(10ng/ml),proBDNF(10ng/ml)+sortilin-FC(20ng/ml),或BSA(10ng/ml)的细胞培养液进行培养,采用BrdU标记法观察海马神经元增殖情况,用TUNEL法检测凋亡细胞。
结果
1.基因重组proBDNF蛋白在大肠杆菌中的表达及活性鉴定
扩增出的大鼠proBDNF cDNA片段克隆进了原核表达载体,经酶切和核酸测序鉴定,得到了正确的重组质粒pET-proBDNF,并在大肠杆菌中获得了表达。纯化后的蛋白经考马氏亮蓝染色呈单一条带,用抗proBDNF的抗体进行western blot分析证明目的蛋白获得了表达。免疫组化结果提示,基因重组proBDNF蛋白能够促进PC12细胞凋亡,而亲合纯化的羊抗proBDNF抗体能够中和proBDNF的促细胞凋亡作用。
2.proBDNF对老龄鼠认知功能影响
Morris水迷宫测试实验结果显示,从Morris水迷宫实验第3天起,proBDNF注射组平均逃避潜伏期明显长于对照组;而抗proBDNF组平均逃避潜伏期比对照组短。各组之间游泳速度相差不显著。在空间探索实验中,proBDNF组在平台所在象限游泳时间的百分比明显比对照组小,动物入水后无目的游动,而抗proBDNF组在平台所在象限游泳时间的百分比明显比对照组增加,其运动轨迹主要集中于原平台所在位置。
3.proBDNF对老龄鼠海马神经发生的影响
免疫组化结果显示,术后第7天,典型的BrdU阳性细胞内有深棕黄色的颗粒,这些阳性细胞大部分位于颗粒细胞层与门区之间,即所谓的下颗粒区,往往紧密排列、成簇出现,细胞形状不规则。术后第28天,BrdU阳性细胞呈椭圆型或圆形,形态接近颗粒细胞,多数位于颗粒细胞层,也有零星细胞位于海马门区。
术后第7天及第28天proBDNF组每张切片BrdU阳性细胞数均分别明显低于BSA对照组(p＜0.01),而抗proBDNF组则明显高于BSA对照组(p＜0.01)。术后第28天,proBDNF组、抗proBDNF组及对照组,各组中BrdU阳性细胞数与术后第7天同组比较均明显下降(其中proBDNF组下降最明显),分别为术后第7天的50%、38%和60%。
免疫荧光三标法对术后第7天和第28天BrdU阳性细胞进行鉴定,结果发现proBDNF组、抗proBDNF组以及BSA组,三组中各细胞类型的百分比无显著性差异。
4.proBDNF对老龄鼠海马突触可塑性的影响
术后第28天免疫印迹结果显示,proBDNF组海马synapsinⅠ以及pCREB的含量分别较BSA对照组明显减少(p＜0.01),而抗proBDNF组海马synapsinⅠ以及pCREB的含量则明显增加(p＜0.01)。
5.proBDNF对培养的海马神经元增殖和凋亡的影响
对于野生型鼠培养海马神经元,与对照组比较,proBDNF组BrdU阳性细胞百分比明显降低(p＜0.01)、TUNEL阳性细胞百分比明显增加(p＜0.01),而proBDNF+sortilin-FC组BrdU阳性细胞百分比、TUNEL阳性细胞百分比与对照组比较无显著差异。
P75~(NTR)基因敲除鼠培养神经元中,proBDNF组BrdU阳性细胞百分比、TUNEL阳性细胞百分比与对照组比较无显著差异。
结论
1.本研究成功构建了表达基因重组大鼠proBDNF的原核表达载体,基因重组大鼠proBDNF蛋白在大肠杆菌中获得了表达和纯化,所获得的基因重组蛋白具有较好的生物学活性。
2.通过Morris水迷宫实验,证实proBDNF能够降低老龄鼠的学习记忆功能,而阻断内源性proBDNF后能改善老龄鼠的学习记忆能力。
3.proBDNF可抑制海马细胞增殖、降低新生细胞的存活率,但对细胞分化无影响。
4.proBDNF可降低海马synapsinⅠ和pCREB蛋白的含量,提示proBDNF可降低老龄鼠突触可塑性。
5.proBDNF抑制体外培养的海马神经元的增殖、促进细胞凋亡,proBDNF这种作用需要P75~(NTR)及sortilin的参与。
6.proBDNF可能通过抑制老龄鼠海马的神经发生、降低海马突触可塑性,从而降低老龄鼠的学习记忆功能。
Background
Alzheimer'disease(AD) is the most common form of dementia in later life,and a major cause of disability and death in the elderly.Currently there are more than 12 million individuals affected with AD worldwide,and it is projected that the prevalence will nearly quadruple in the next 50 years,by which time approximately 45 million will be afflicted with the disease.It is a huge burden for the families and the society.
China has been facing a very serious and irreversible situation of population aging during 21st century.Since 1999 China's population has become aged with the most amount of old people in the world.According to calculation based on the current prevalence data,it is estimated that there will be 8 to 12 million AD patients in China by 2050.
Alzheimer's disease is associated with the loss of neurons in areas of the brain that are vital to memory and other mental abilities,like the hippocampus.In elderly humans, imaging studies have shown hippocampal atrophy.It is of great importance and interest to develop effective approaches which are able to prevent the incidence of neuron loss. Neurogenesis in adult mammals occurs in several regions,including the forebrain subventricular zone(SVZ) and the dentate gyrus of the hippocampal formation. Hippocampal neurogenesis occurs throughout the adulthood and is important for learning and memory,but it declines with age.Reduced neurogenesis in the aged hippocampus has been shown to be associated with cognitive deficits.Neurogenesis maybe a potential therapeutic strategy for AD.
Brain-derived neurothrophic factor(BDNF) can promote the proliferation, differentiation and survival of neuron.BDNF can enhance the activity-dependent synaptic plasticity.It is recently confirmed that the precursor of BDNF(proBDNF) is the main expressing product of BDNFmRNA outside the cell.proBDNF distributes widely in the adult animal,especially in the central nervous system.The uncleaved precursor may play a different role from that of mature BDNF.It has been shown that a single amino acid mutation(Val66Met) in the proregion of BDNF affects the sorting of the molecule into the nerve terminals,retards activity-dependent secretion and reduces learning functions of the hippocampus.Under pathological conditions,such as aging and early stage of AD,the proBDNF and P75~(NTR) expression are upregulated.All of these indicate that proBDNF is not merely precursor of BDNF and may have important roles in the development of cognition impairment.
It is important for the prevention of AD to study the roles of proBDNF in hippocampal neurogenesis and synaptic plasticity.Thus in the present study,there are main contents including expression,purification of cleave -resistant recombinant proBDNF protein,and study on its functional characterization.Effects of proBDNF on the cognition function in aged mice were observed.By in vivo and in vitro study,we evaluated the effects of proBDNF on hippocampal neurogenesis and synaptic plasticity,and investigated the mechanism of the effects of proBDNF on cognition function.
Method
1.Expression,purification of recombinant proBDNF protein in E.coli.and its functional characterization
The cDNA fragment from proBDNF was obtained by standard PCR method with a full-length rat mutated proBDNF cDNA as template,and was inserted into plasmid pET-28a by means of gene rearrangement.The recombinant plasmid pET-proBDNF was identified by restriction endonuclease analysis and DNA sequencing.The cloned pET-proBDNF plasmid was transformed into E.coli host strain,BL21.Following induction by IPTG,the recombinant protein was expressed and then purified by Ni-NAT affinity chromatography under denaturing conditions.The interest protein was viewed by SDS-PAGE,further characterized by western blot.The apoptosis of PC12 cells was evaluated by DAPI assay.
2.Effects of proBDNF on cognition function in aged mice
Thirty aged C57BL/6J mice(18months old)were randomly divided in to three groups: proBDNF group,anti-proBDNF group,or bovine serum albumin(BSA) group(n=10).A Alzet osmotic minipump was connected to right hippocampus of the mouse.Pumps were filled with proBDNF(1μg/μl),sheep antibody to proBDNF(1μg/μl),or BSA(1μg/μl), respectively.Mice received the injection for 6 days at the speed of 0.2μl/h.21days after surgery,the animals were subjected for Morris Water Maze to test mean escape latency, swimming speed and percentage of time spent in the target quardrant.
3.Effects of proBDNF on hippocampal neurogenesis in aged mice.
Thirty 18-month-old C57BL/6J mice were used in this experiment.Animals received proBDNF,sheep antibody to proBDNF or BSA as described previously in step 2.BrdU(50 mg/kg,i.p.) was injected twice per day for 6 days immediately after surgery.7days and 28 days postsurgery,immunohistochemistry was processed to examine the BrdU positive cells, and immunofluoresent triple labeling was processed to examine the phenotype of the newly generated cells.
4.Effects of proBDNF on hippocampal synaptic plasticity in aged mice.
Fifteen 18-month-old C57BL/6J mice were used in this experiment.Animals received proBDNF,sheep antibody to proBDNF or BSA as described previously in step 2.28 days postsurgery,western blot were used to observe changes of the synaptic plasticity marker-pCREB and synapsin I.
5.Effects of proBDNF on the proliferation and apoptosis of cultured hippocampal neuron.
The primary hippocampal cell cultures were prepared from 1-day-old female P75~(NTR) knocked out mice and their wild-type littermates.Cells were co-cultured with cleaved resistant proBDNF,proBDNF+sortilin-FC,or BSA,respectively.Proliferation was tested by immunohistochemstry on BrdU,and apoptosis of hippocampal neuron was detected by TUNEL assay.
Results
1.Expression,purification of recombinant proBDNF protein in E.coli.and its functional characterization
The rat proBDNF cDNA was amplified and cloned into prokaryotic expression vector. The restriction endonuclease analysis and DNA sequencing proved that the plasmid pET-proBDNF was obtained.The recombinant protein was expressed in E.coli system. After Coomassie brilliant blue staining,the recombinant protein showed an exclusive band; western blot analysis with anti-proBDNF antibody supported that the expressed protein was recombinant proBDNF.The recombinant rat proBDNF protein could enhance the apoptosis of PC12 cells.Affinity purified antibody to proBDNF could neutralize the effect of proBDNF
2.Effects of proBDNF on cognition function in aged mice
Compared with BSA control group,proBDNF group had longer mean escape latency (p＜0.05),while the mean escape latency in antiproBDNF group was shorter(p＜0.05).When it comes to swimming speed,there had no difference between each group.Compared with control group,mice in proBDNF group spent less time in the target quadrant,while mice in anti-proBDNF group spent more time in the target quadrant(p＜0.05).
3.Effects of proBDNF on hippocampal neurogenesis in aged mice.
7days and 28days postsurgery,proBDNF group had less BrdU positive cells in dentate gyrus(p＜0.01),while antiproBDNF had more BrdU positive cells(p＜0.01),compared with control group,respectively.After 28days postsurgery,the BrdU positive cells decreased in all the groups,but proBDNF decreased the most dramatically.Immunofluoresent triple labeling showed that there had not difference of phenotype of BrdU positive cells between each group.
4.Effects of proBDNF on hippocampal synaptic plasticity in aged mice.
28days postsurgery,western blot showed that synapsin I and P-CREB in hippocampus were lower in proBDNF group than that of control group(p＜0.01).But anti-proBDNF group had more synapsin I and pCREB,compared with control group(p＜0.01)
5.Effects of proBDNF on the proliferation and apoptosis of cultured hippocampal neuron.
The number of BrdU positive cells in wild type mice decreased significantly in proBDNF group(p＜0.01,compared with control group),but there had no difference between proBDNF+sortilin-Fc group and contral group.In P75~(NTR) knockout mice,the BrdU positive cells in proBDNF group was the same as the control group.
On the contrary,the number of TUNEL positive cells in wild type mice increased significantly in proBDNF group(p＜0.01,compared with control group),while there had no difference between proBDNF+sortilin-Fc group and control group.In P75~(NTR) knockout mice,both the control group and proBDNF group had the same percentage of TUNEL positive cell.
Conclusions
1.The prokaryotic expression vector for rat proBDNF is successfully constructed.The recombinant rat proBDNF protein can be expressed and purified in E.coli.and has a good biological activity.
2.proBDNF can suppress the learning and memory ability of aged mice.It indicates that proBDNF plays a different role from that of mature BDNF.
3.proBDNF suppressed the proliferation and survival of hippocampal neuron in dentate gyrus in aged mice.
4.proBDNF downregulated the expression of pCREB and synapsin I protein in hippocampus of aged mice.
5.proBDNF can inhibit the proliferation of neurons in dentate gyrus and initiate cell death.Interaction of proBDNF with both receptors of sortilin and P75~(NTR) on the cell surface is required for these effects.
6.proBDNF can suppress the learning and memory ability of aged mice by inhibiting the hippocampal neurogenesis and downregulating the expression of pCREB and synapsin I protein in hippocampus.
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