轴突生长抑制因子重组疫苗对阿尔茨海默症APP/PS1转基因模型小鼠的预防
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摘要
阿尔茨海默症(Alzheimer's disease:AD)又名老年痴呆症是引发痴呆的最常见疾病。表现为记忆、智力、判断能力、情感障碍和行为失常甚至发生意识模糊等,其显著的病理学特征是脑内出现老年斑、神经元纤维缠结、和神经元和突触丢失。随着人口老龄化的加重阿尔茨海默症越来越受到人们的重视。其发病机制尚为数个假说,其中淀粉样前体蛋白(Amyloid precursor protein; APP)水解产物Amyloidβ(Aβ)蛋白为阿尔茨海默症发病首要原因的假说占主导地位。目前的药物治疗只能减轻患者症状并不能对AD起到根本性治疗作用。免疫治疗主要集中针对Ap蛋白,虽然脑膜脑炎副作用的产生成为了Aβ疫苗进入临床的阻碍,但疫苗可降低病人脑内老年斑改善病人学习记忆异常的事实是人们看到了免疫治疗治愈AD疾病的希望。轴突生长抑制蛋白(neurite outgrowth inhibitors; NOIs)一类以抑制中枢神经系统损伤后轴突再生为主要功能的蛋白。Tenascin-R(TN-R)、Tenascin-C(TN-C)、髓鞘相关糖蛋白(myelin-associated glycoprotein, MAG)、少突胶质细胞-髓鞘相关糖蛋白(oligodendrocyte-myelin glycoprotein; OMGP)、Nogo、受体样蛋白酪氨酸磷酸酶P(The receptor-type protein tyrosine phosphataseβ; RPTPβ)均为轴突生长抑制因子成员。NOIs主要聚集于中枢神经元的郎飞氏结处,而研究表明在AD疾病中占有重要地位的APP蛋白亦聚集表达与中枢神经系统的郎飞氏结处,郎飞氏结是有髓神经纤维的重要功能位置,除上述两种蛋白外,大量在神经细胞功能中占有重要地位的离子通道亦聚集于此处。我们推测NOIs蛋白可在郎飞氏结处通过与APP得相互作用,影响其水解过程即Aβ蛋白的产生从而影响AD疾病的发生发展。此外,由单个NOI蛋白抗体或数个NOIs蛋白免疫小鼠可促进体内外中枢神经的再生。我们推测抑制NOIs的功能亦能改善AD疾病中神经元的退行性变达到预防或治疗AD的目的。
构建由数个NOIs蛋白片段重组的DNA疫苗,免疫AD转基因小鼠模型来检验抑制NOIs对AD的预防或治疗作用。我们构建了三个由NOIs数个蛋白抗原片段不同组合的重组疫苗,通过DNA疫苗肌肉免疫的方式检测其在体内抗体的产生。行为学检测了疫苗对AD模型小鼠的学习记忆改善情况,并检测了疫苗对模型小鼠脑内Aβ老年斑沉积的改变。我们发现其中一个疫苗PcDNA-V2可有效减少模型小鼠脑内老年斑的沉积,但同时看到单纯DNA疫苗肌肉免疫小鼠虽能产生抗体但抗体效价不高。为了提高抗体确保疫苗实验有效,我们包被了与PcDNA-V2含有相同抗原片段的痘病毒疫苗(vaccinia virus vaccine2:VV-V2),通过肌肉注射DNA疫苗初免痘苗病毒加强的的方式免疫APP/PS1转基因模型小鼠。通过对小鼠血清中抗体检测,我们发现DNA疫苗与痘苗病毒疫苗联合免疫的方式可产生有效且较高的抗体,同时并未在免疫小鼠脑内发现炎症副反应。水迷宫、开放旷场等行为学检测发现疫苗能够有效的抑制转基因AD模型小鼠的学习记忆障碍及情绪异常,随后用三种方式检测了AD发病中占主流假说的Aβ蛋白不同的表达形式,发现虽然疫苗并未改变Ap蛋白总量,却显著降低了Ap蛋白两种主要构成成分Aβ42和Aβ40之间的比值,在Ap蛋白总量不变的情况下,Aβ42和Aβ40的比值升高被认为是AD的危险发病因素之一；此外发现疫苗能够有效降低免疫小鼠海马皮质不溶性Aβ蛋白表达形式老年斑的产生；可溶性的Ap蛋白寡聚体被认为是Ap蛋白所有表达形式中最早对神经元产生毒性的,我们发现疫苗也可有效抑制模型小鼠脑内可溶性寡聚体的异常升高。随后对海马皮质的电镜检测中发现疫苗亦明显抑制了AD模型小鼠的神经元退行性改变。
以上结果均证实在预防实验中NOls重组疫苗能有效改善AD转基因模型小鼠的行为学异常,抑制其脑内神经元退行性变,并降低模型小鼠脑内Ap蛋白的表达。虽然疫苗的具体作用位点及机制尚需进一步实验证实,但推测其可能为通过与APP相互作用改变Ap蛋白表达,且我们初步实验结果与假设相符。这一发现为AD治疗提供了新思路,并为NOIs重组疫苗在其它神经退行性变疾病中的应用提供了可能。
Alzheimer's disease is a chronic neurodegenerative disease, which causes a progressive loss in learning and memory capabilities and eventually results in dementia. The deposition of amyloid P plaques、neurofibrillary tangles and injury and lost in neuron in center nervous system are the main characteristics in AD patients. As the increasing number of old people in China. AD take more burdens on the patients's family and the whole society and this disease deserved more and more attention. However, most of the medicines used in the therapeutic of AD produce little effect on curing this disease. According to previous studies, immunotherapy of Alzheimer's disease mostly focused on decreasing amyloidβbut the inflammation in the therapeutic mice brain became the obstacle of clinical use of vaccine. The olidendrocyte-and myelin-related neurite outgrowth inhibitors include Tenascin R (TN-R), Tenascin-C (TN-C), myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein(OMGP), Nogo, The receptor-type protein tyrosine phosphataseβ(RPTPβ). They are a group of proteins mainly inhibiting the outgrowth of neuron and axons after injury in central nevous system. They were mainly clustered in the nodes of Ranvier. APP protein was also found clustered in the nodes of Ranvier in central nervous system. We suppose NOIs interact with APP protein and change the enzymolysis of APP influencing the Aβexpression and the onset, development of Alzheimer's disease. What's more, the antibody of single NOI or immunization with several fagments of NOIs could promote the regeneration of neurons in central nervers system. Previous study also identify NOIs could directly or indirectly influence the expression of Aβprotein.
We designed three recombinant DNA vaccines comprising the specific inhibitory domains of neurite outgrowth inhibitors and did preventive test in a co-transgenic mice model. The mice in vaccine group were concequently immunized every week with naked DNA vaccine though intramuscular injection. The blood was collected and antibody was detected by Elisa test. Morris Water Maze was used to test the learing and memory ability. Immunohistochemistry test was used to test the deposition numbers and area taken up of Aβin hippocampus and cortex. The better effect of preventive vaccine PcDNA-V2 was chosen for further test. We also find the naked DNA immunization tragedy evoked low level antibody. So we construct the vaccinia virus vaccine and immunized the mice by co-immunization of DNA and vaccinia virus vaccine. Blood of immunized mice in each group were collected. Open filed test. Morris Water Maze and new object recognition test were used to test the learing and memory ability and mood behavior changes in every group. Elisa test was used to examine the expression of Aβ42 and 40 total proteins. Immunohistochemistry test was used to test the deposition numbers and area taken up of Aβin hippocampus and cortex. Western-blot was appling to detect the expression of soluble Aβoligomer. Immunohistochemistry and HE were used to test if there any inflammation in the brain of immunized mice. Western blot was used to exmine the expression of NOIs in the APP/PS1 co-transgenic mice over-expressing APP protein.
PcDNA-V2 showed an effection of decreasing the expression of Aβdeposition in the naked DNA vaccine test. The vaccinia virus vaccine of PcDNA-V2 was contructed. DNA prime boost vaccination tragedy induced strong immune responses and effective antibodies against the four fragments in immune serum of treated mice by DNA prime-vaccinia virus boost regimen. Vaccines prevented neurons necrosis and axonal injury in the brains of treated model mice and protected the model mice from behavioral deficits. It also decreased the ratio of Aβ42 to Aβ40 in co-transgenic mice brain which is thought to play an important role in the risk of AD. The deposition of Aβplaques was significantly decreased in vaccine group than in the placebo and vehicle group. The soluble Aβoligomer in vaccine group was decreased significantly according to IP-western result. There was no lymphocytic infiltration in brains of model mice. There was an obvious change of TN-R and OMGP protein in APP/PS1 transgenic mice.
The results suggested that immunotherapy with multiple specific domains of oligodendrocyte-and-myelin-related neurite outgrowth inhibitors might be a promising approach for Alzheimer's disease and the degenerative diseases of central nervous system. The vaccine was supposed to interact with APP to infect the onset and development of Alzheimer's disease.
构建由数个NOIs蛋白片段重组的DNA疫苗,免疫AD转基因小鼠模型来检验抑制NOIs对AD的预防或治疗作用。我们构建了三个由NOIs数个蛋白抗原片段不同组合的重组疫苗,通过DNA疫苗肌肉免疫的方式检测其在体内抗体的产生。行为学检测了疫苗对AD模型小鼠的学习记忆改善情况,并检测了疫苗对模型小鼠脑内Aβ老年斑沉积的改变。我们发现其中一个疫苗PcDNA-V2可有效减少模型小鼠脑内老年斑的沉积,但同时看到单纯DNA疫苗肌肉免疫小鼠虽能产生抗体但抗体效价不高。为了提高抗体确保疫苗实验有效,我们包被了与PcDNA-V2含有相同抗原片段的痘病毒疫苗(vaccinia virus vaccine2:VV-V2),通过肌肉注射DNA疫苗初免痘苗病毒加强的的方式免疫APP/PS1转基因模型小鼠。通过对小鼠血清中抗体检测,我们发现DNA疫苗与痘苗病毒疫苗联合免疫的方式可产生有效且较高的抗体,同时并未在免疫小鼠脑内发现炎症副反应。水迷宫、开放旷场等行为学检测发现疫苗能够有效的抑制转基因AD模型小鼠的学习记忆障碍及情绪异常,随后用三种方式检测了AD发病中占主流假说的Aβ蛋白不同的表达形式,发现虽然疫苗并未改变Ap蛋白总量,却显著降低了Ap蛋白两种主要构成成分Aβ42和Aβ40之间的比值,在Ap蛋白总量不变的情况下,Aβ42和Aβ40的比值升高被认为是AD的危险发病因素之一；此外发现疫苗能够有效降低免疫小鼠海马皮质不溶性Aβ蛋白表达形式老年斑的产生；可溶性的Ap蛋白寡聚体被认为是Ap蛋白所有表达形式中最早对神经元产生毒性的,我们发现疫苗也可有效抑制模型小鼠脑内可溶性寡聚体的异常升高。随后对海马皮质的电镜检测中发现疫苗亦明显抑制了AD模型小鼠的神经元退行性改变。
以上结果均证实在预防实验中NOls重组疫苗能有效改善AD转基因模型小鼠的行为学异常,抑制其脑内神经元退行性变,并降低模型小鼠脑内Ap蛋白的表达。虽然疫苗的具体作用位点及机制尚需进一步实验证实,但推测其可能为通过与APP相互作用改变Ap蛋白表达,且我们初步实验结果与假设相符。这一发现为AD治疗提供了新思路,并为NOIs重组疫苗在其它神经退行性变疾病中的应用提供了可能。
Alzheimer's disease is a chronic neurodegenerative disease, which causes a progressive loss in learning and memory capabilities and eventually results in dementia. The deposition of amyloid P plaques、neurofibrillary tangles and injury and lost in neuron in center nervous system are the main characteristics in AD patients. As the increasing number of old people in China. AD take more burdens on the patients's family and the whole society and this disease deserved more and more attention. However, most of the medicines used in the therapeutic of AD produce little effect on curing this disease. According to previous studies, immunotherapy of Alzheimer's disease mostly focused on decreasing amyloidβbut the inflammation in the therapeutic mice brain became the obstacle of clinical use of vaccine. The olidendrocyte-and myelin-related neurite outgrowth inhibitors include Tenascin R (TN-R), Tenascin-C (TN-C), myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein(OMGP), Nogo, The receptor-type protein tyrosine phosphataseβ(RPTPβ). They are a group of proteins mainly inhibiting the outgrowth of neuron and axons after injury in central nevous system. They were mainly clustered in the nodes of Ranvier. APP protein was also found clustered in the nodes of Ranvier in central nervous system. We suppose NOIs interact with APP protein and change the enzymolysis of APP influencing the Aβexpression and the onset, development of Alzheimer's disease. What's more, the antibody of single NOI or immunization with several fagments of NOIs could promote the regeneration of neurons in central nervers system. Previous study also identify NOIs could directly or indirectly influence the expression of Aβprotein.
We designed three recombinant DNA vaccines comprising the specific inhibitory domains of neurite outgrowth inhibitors and did preventive test in a co-transgenic mice model. The mice in vaccine group were concequently immunized every week with naked DNA vaccine though intramuscular injection. The blood was collected and antibody was detected by Elisa test. Morris Water Maze was used to test the learing and memory ability. Immunohistochemistry test was used to test the deposition numbers and area taken up of Aβin hippocampus and cortex. The better effect of preventive vaccine PcDNA-V2 was chosen for further test. We also find the naked DNA immunization tragedy evoked low level antibody. So we construct the vaccinia virus vaccine and immunized the mice by co-immunization of DNA and vaccinia virus vaccine. Blood of immunized mice in each group were collected. Open filed test. Morris Water Maze and new object recognition test were used to test the learing and memory ability and mood behavior changes in every group. Elisa test was used to examine the expression of Aβ42 and 40 total proteins. Immunohistochemistry test was used to test the deposition numbers and area taken up of Aβin hippocampus and cortex. Western-blot was appling to detect the expression of soluble Aβoligomer. Immunohistochemistry and HE were used to test if there any inflammation in the brain of immunized mice. Western blot was used to exmine the expression of NOIs in the APP/PS1 co-transgenic mice over-expressing APP protein.
PcDNA-V2 showed an effection of decreasing the expression of Aβdeposition in the naked DNA vaccine test. The vaccinia virus vaccine of PcDNA-V2 was contructed. DNA prime boost vaccination tragedy induced strong immune responses and effective antibodies against the four fragments in immune serum of treated mice by DNA prime-vaccinia virus boost regimen. Vaccines prevented neurons necrosis and axonal injury in the brains of treated model mice and protected the model mice from behavioral deficits. It also decreased the ratio of Aβ42 to Aβ40 in co-transgenic mice brain which is thought to play an important role in the risk of AD. The deposition of Aβplaques was significantly decreased in vaccine group than in the placebo and vehicle group. The soluble Aβoligomer in vaccine group was decreased significantly according to IP-western result. There was no lymphocytic infiltration in brains of model mice. There was an obvious change of TN-R and OMGP protein in APP/PS1 transgenic mice.
The results suggested that immunotherapy with multiple specific domains of oligodendrocyte-and-myelin-related neurite outgrowth inhibitors might be a promising approach for Alzheimer's disease and the degenerative diseases of central nervous system. The vaccine was supposed to interact with APP to infect the onset and development of Alzheimer's disease.
引文
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