鞘氨醇激酶1对阿尔茨海默病APP/PS1动物模型保护作用的研究
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摘要
第一部分鞘氨醇激酶1高表达对APP/PS1双转基因AD模型鼠的作用
目的：异常产生和沉积的淀粉样-β蛋白（Aβ）是阿尔茨海默病（AD）发病机制和痴呆的重要原因。有证据表明鞘氨醇-1-磷酸（S1P）/神经酰胺变阻器失衡可能是AD的一种发病机制。本研究的目的是探讨鞘氨醇激酶1的高表达对APP/PS1转基因阿尔茨海默病模型小鼠的影响。
方法：由于Sphk1是S1P/ceramide变阻器之间平衡的关键酶，因此本研究中我们采用立体定位注射的方法将靶基因为Sphk1重组腺病毒介导的载体（rAV-Sphk1）注射至海马以评估其对APPsw/PS1双转基因小鼠（APP/PS1）AD模型鼠的作用。用激光共聚焦显微镜观察淀粉样蛋白的沉积；western blot法检测SphK1的表达；酶联免疫吸附试验评估淀粉样蛋白的分泌；水迷宫实验检测小鼠行为学的改变。
结果：立体定位注射rAV-Sphk1四个星期后APP/PS1小鼠出现Sphk1蛋白表达升高。同时降低Aβ蛋白的沉积和细胞凋亡程度，水迷宫试验中，小鼠潜伏期明显缩短，且首次穿越第三象限的平均时间及找到平台的次数明显优于其他两组。
结论：这些结果表明，Sphk1高表达可以降低老年斑的沉积及环节小鼠行为学的损害，对APP/PS1小鼠起到一定的保护作用。因此，Sphk1高表达在AD的发病机制中起着重要的治疗的作用，通过基因水平干预Sphk1的表达有可能成为治疗AD的新手段。
第二部分鞘氨醇激酶1高表达对APP/PS1双转基因AD鼠保护作用的机制
目的：第一部分研究发现鞘氨醇激酶1高表达可以降低小鼠老年斑的沉积及缓解其行为学的损害，但是我们尚未清楚Sphk1保护作用的机制。因此本部分的研究目的就是探索鞘氨醇激酶1高表达对APP/PS1双转基因AD鼠保护作用的可能机制。
方法：本部分我们采用Western blot法检测Caspase-3蛋白的表达； TUNEL法检测细胞的凋亡。 s1pr1，s1pr3mRNA的表达则通过实时Real time PCR来测定。酶联免疫吸附试验旨在评估CER，S1P的分泌。超微电子显微镜来检测APP/PS1双转基因小鼠模型海马超微结构。
结果：立体定位注射rAV-Sphk1四个星期后APP/PS1小鼠出现cer表达减少，S1P表达明显升高，且ceramide/S1P比例下降。电镜结果显示海马超微结构未见明显的细胞核核质边缘化。且Sphk1高表达后caspase-3表达明显下降。而S1Pr1表达升高，且突触后膜SNAP-25蛋白的表达增加突触的活性。
结论：这些研究结果表明，Sphk1可以通过capases-3途径抑制细胞凋亡，同时上调S1P受体（S1P-G蛋白偶联受体）及SNAP-25蛋白的表达来提高突触的活性。
第三部分小分子RNA干扰鞘氨醇激酶1对APP/PS1双转基因AD鼠的作用
目的：阿尔茨海默病是一种随着年龄逐渐进展并最终导致记忆、行为、人格改变的一种神经退行性疾病。之前的研究发现阿尔茨海默病患者存在鞘氨醇代谢异常。且前两部分研究结果显示鞘氨醇激酶1高表达可以有效地降低老年斑的沉积，及凋亡的发生，可以显著改变APP/PS1模型鼠的行为学损害，其从正面证实了鞘氨醇激酶1高表达对APP/PS1双转基因AD模型鼠的保护作用。本研究的目的就是为了从反面证实降低鞘氨醇激酶1的表达能否加快阿尔茨海默病动物模型中老年斑的沉积及损害其学习和记忆能力等的关系。
方法：本研究中我们采用小分子干扰鞘氨醇激酶1基因的腺病毒载体进行海马立体定位注射转染APP/PS1小鼠，4周后检测其对APP/PS1小鼠的影响。采用RT-PCR检测鞘氨醇激酶1mRNA及及Western-blot检测鞘氨醇激酶1及caspase-3蛋白的表达，通过Elisa检测神经酰胺及S1P的含量，采用免疫荧光及Elisa来检测老年斑的沉积及水迷宫来检测小鼠行为学的改变。
结果：干预组和对照组的鞘氨醇激酶1mRNA及蛋白表达存在明显的差异。干预组小鼠老年斑沉积速度加快，且其学习及记忆能力损害明显加重。
结论：siRNA-sphk1的重组腺病毒构建成功,且具有抑制Sphk1蛋白表达的功能,该基因沉默后,促进了APP/PS1双转基因AD模型鼠老年斑的沉积及其学习和记忆能力的损害。
第四部分小分子RNA干扰鞘氨醇激酶1对APP/PS1双转基因AD鼠作用机制的研究
目的：观察腺病毒介导的鞘氨醇激酶1低表达对APP/PS1双转基因AD模型鼠海马区凋亡的影响，进一步明确sphk1低表达对AD模型鼠作用的可能机制。
方法立体定位注射法将携带siRNA-sphk1的腺病毒载体注射至APP/PS1双转基因AD模型鼠海马区,以1X1011pfu/ml的病毒总量分2点注射，对照组海马内注射等量生理盐水，四周后进行检测，观察海马组织凋亡的改变，以及caspase-3表达的改变。
结果：注射Sphk1-siRNA的小鼠30d后海马区与对照组相比，转染后TUNEL果显示凋亡程度显著提高，且western-blot结果显示caspase-3表达显著增多。
结论：上述结果表明, siRNA-sphk1的重组腺病毒成功沉默sphk1基因后,促进了APP/PS1双转基因AD模型鼠海马区的凋亡。
Part I. Overexpression of Sphingosine Kinase-1Rescues TransgenicMouse Model of Alzheimer’s Disease from Neurotoxicity ofAmyloid-β (Aβ) protein
Objective: Aberrant production and accumulation of amyloid-β（Aβ）protein is central tothe pathogenesis of Alzheimer’s disease (AD) and has a causal role in dementia. Evidenceshowed that imbalance of sphingosine1-phosphate (S1P)/ceramide rheostat may be part ofa mechanism. The aim of this study was to explore the effects of overexpression ofsphingosine kinase-1on the APP/PS1transgenic mouse model of Alzheimer’s Disease.
Methods: In this study, APPsw/PS1double-transgenic（APP/PS1）mice were adopted andreceived an intra-hippocampal injection of recombinant adenovirus-mediated vectorstargeting Sphk1gene(rAV-Sphk1) to evaluate the role of sphingosine kinase-1(Sphk1), acritical regulator of the balance between S1P/ceramide rheostat, in the pathologicalprogression of AD. Confocal microscopy was used to evaluate the disposition of amyloidprotein. The protein expression of sphk1were determined by Western blot. Elisa wasdesigned to assess the secretion of amyloid protein. Mirror water maze was used to detectthe damage of behavior of APP/PS1double transgenic mouse model.
Results: Administration of rAV-Sphk1to the APP/PS1mice four weeks later exhibitedoverexpression of Sphk1protein coupled with decreased deposition of Aβ protein followedby improved learning and memory abilities. Conclusions: These results demonstrate that overexpression of Sphk1could efficientlyattenuate the pathological damage of AD. Therefor, Sphk1overexpression mitigated thepathological damage of AD, establishing a critical role of Sphk1overexpression for AD andSphk1gene delivery would be a novel strategy for the treatment of AD.
Part II. The mechanism of the protective effects of sphingosine kinase1on the of APP/PS1double transgenic AD mice
Objective: The first part of the study found that sphingosine kinase1over-expression canreduce the deposition of senile plaques in mice and mitigate the damage of their behavior,but we have not yet to clear the way of Sphk1protective effect. The purpose of this part isto explore the mechanism of the protective effects of sphingosine kinase1on the APP/PS1double transgenic AD mice.
Methods: In this section, Caspase-3protein expression was assessed by Western blot.TUNEL was used to assay the degree of apoptosis. The expression of s1pr1, s1pr3mRNAwere measured by real-time PCR. Enzyme-linked immunosorbent assay (ELISA) designedto evaluate the CER, S1P secretion. Ultrafine electron microscopy to detect thehippocampal ultrastructure of APP/PS1double transgenic mouse.Results: Four weeks after stereotactic injection, the APP/PS1mice showed a decline inceramide/S1P proportion coupled with a lower degree of apoptosis. And Sphk1over-expression could inhibite the caspase-3expression significantly. Elevated S1Pr1expression and postsynaptic membrane SNAP-25protein expression increased synapticactivity.
Conclusion: These findings suggest that overexpression of Sphk1could suppress apoptosisvia the capases-3pathway and up-regulate synaptic activity by SNAP-25and s1p receptor(s1p-GPCRs).
Part III. Effects of Small Interfering RNA Targeting SphingosineKinase-1Gene On The Animal Model Of Alzheimer’s Disease
Objective：Alzheimer’s disease (AD) is an age-related, progressive neurodegenerativedisorder that occurs gradually and results in memory, behavior, and personality changes.Abnormal sphingolipid metabolism was reported in AD previously. And our previous studyshowed that：over-expression of Sphk1could suppress apoptosis and relieve the depositionof Aβ protein,which demonstrated from the good side the protective role of Sphk1in theAPP/PS1double transgenic mouse.The aim of this study was to explore the effects ofdownregulating the expression of Sphk1expression by the way of small interferingRNA(siRNA) on the APP/PS1double transgenic mouse.
Mehtods: An adenovirus vector that expressed small interfering RNA(siRNA)against theSphk1gene（Sphk1-siRNA）was designed, then effects of Sphk1-siRNA on the APP/PS1mouse4weeks after treatment with sphk1-siRNA hippocampcal injection was examined.Sphk1protein expression were confirmed using Western blot and ceramide content coupledwith S1P secretion was evaluated by enzyme-linked immunosorbent assay (Elisa). Aβ loadwas detected by Immunohistochemical staining and ELISA. Morris water maze wasadopted to test the learning and memory ability of the APP/PS1mice.Results: A significant difference in the expression of Sphk1protein and mRNA wasobserved between the siRNA group and the control group. Aβ load in transfected mice wasaccelerated in vivo, with significant aggravation of the learning and memory ability.
Conclusion: The results show that the recombinant adenovirus vector containing thesphk1gene was successfully constructed, which can accelerate the burdern of Aβ load andthe learning and memory ability, silence SPhK1gene in vivo. The Sphk1gene modulationin the in the animal model of AD may be important for the treatment of AD.
Part IV. The mechanism of Small Interfering RNA TargetingSphingosine Kinase-1Gene On Apoptosis of The Animal Model OfAlzheimer’s Disease
Objective To observe the effect of the recombinant adenovirus vector that expressed smallinterfering RNA(siRNA)against the sphk1gene（Sphk1-siRNA）on the apoptosis ofAPP/PS1double transgenic mouse.
Methods After the recombinant adenovirus vector containing the sphk1gene wassuccessfully constructed，then effect of the recombinant adenovirus vector that expressedsmall interfering RNA(siRNA)against the sphk1gene（siRNA-sphk1）on the apoptosis ofAPP/PS1double transgenic mouse30days after treatment with siRNA-sphk1hippocampcal injection was examined.
Results: Compared with the saline group， the apoptosis degree and the caspase-3expression in the siRNA-sphk1group were markedly increased.Conclusions The results show that the recombinant adenovirus vector containing thesphk1gene was successfully constructed, which can increase the apoptosis of hippocampusin vivo.
目的：异常产生和沉积的淀粉样-β蛋白（Aβ）是阿尔茨海默病（AD）发病机制和痴呆的重要原因。有证据表明鞘氨醇-1-磷酸（S1P）/神经酰胺变阻器失衡可能是AD的一种发病机制。本研究的目的是探讨鞘氨醇激酶1的高表达对APP/PS1转基因阿尔茨海默病模型小鼠的影响。
方法：由于Sphk1是S1P/ceramide变阻器之间平衡的关键酶，因此本研究中我们采用立体定位注射的方法将靶基因为Sphk1重组腺病毒介导的载体（rAV-Sphk1）注射至海马以评估其对APPsw/PS1双转基因小鼠（APP/PS1）AD模型鼠的作用。用激光共聚焦显微镜观察淀粉样蛋白的沉积；western blot法检测SphK1的表达；酶联免疫吸附试验评估淀粉样蛋白的分泌；水迷宫实验检测小鼠行为学的改变。
结果：立体定位注射rAV-Sphk1四个星期后APP/PS1小鼠出现Sphk1蛋白表达升高。同时降低Aβ蛋白的沉积和细胞凋亡程度，水迷宫试验中，小鼠潜伏期明显缩短，且首次穿越第三象限的平均时间及找到平台的次数明显优于其他两组。
结论：这些结果表明，Sphk1高表达可以降低老年斑的沉积及环节小鼠行为学的损害，对APP/PS1小鼠起到一定的保护作用。因此，Sphk1高表达在AD的发病机制中起着重要的治疗的作用，通过基因水平干预Sphk1的表达有可能成为治疗AD的新手段。
第二部分鞘氨醇激酶1高表达对APP/PS1双转基因AD鼠保护作用的机制
目的：第一部分研究发现鞘氨醇激酶1高表达可以降低小鼠老年斑的沉积及缓解其行为学的损害，但是我们尚未清楚Sphk1保护作用的机制。因此本部分的研究目的就是探索鞘氨醇激酶1高表达对APP/PS1双转基因AD鼠保护作用的可能机制。
方法：本部分我们采用Western blot法检测Caspase-3蛋白的表达； TUNEL法检测细胞的凋亡。 s1pr1，s1pr3mRNA的表达则通过实时Real time PCR来测定。酶联免疫吸附试验旨在评估CER，S1P的分泌。超微电子显微镜来检测APP/PS1双转基因小鼠模型海马超微结构。
结果：立体定位注射rAV-Sphk1四个星期后APP/PS1小鼠出现cer表达减少，S1P表达明显升高，且ceramide/S1P比例下降。电镜结果显示海马超微结构未见明显的细胞核核质边缘化。且Sphk1高表达后caspase-3表达明显下降。而S1Pr1表达升高，且突触后膜SNAP-25蛋白的表达增加突触的活性。
结论：这些研究结果表明，Sphk1可以通过capases-3途径抑制细胞凋亡，同时上调S1P受体（S1P-G蛋白偶联受体）及SNAP-25蛋白的表达来提高突触的活性。
第三部分小分子RNA干扰鞘氨醇激酶1对APP/PS1双转基因AD鼠的作用
目的：阿尔茨海默病是一种随着年龄逐渐进展并最终导致记忆、行为、人格改变的一种神经退行性疾病。之前的研究发现阿尔茨海默病患者存在鞘氨醇代谢异常。且前两部分研究结果显示鞘氨醇激酶1高表达可以有效地降低老年斑的沉积，及凋亡的发生，可以显著改变APP/PS1模型鼠的行为学损害，其从正面证实了鞘氨醇激酶1高表达对APP/PS1双转基因AD模型鼠的保护作用。本研究的目的就是为了从反面证实降低鞘氨醇激酶1的表达能否加快阿尔茨海默病动物模型中老年斑的沉积及损害其学习和记忆能力等的关系。
方法：本研究中我们采用小分子干扰鞘氨醇激酶1基因的腺病毒载体进行海马立体定位注射转染APP/PS1小鼠，4周后检测其对APP/PS1小鼠的影响。采用RT-PCR检测鞘氨醇激酶1mRNA及及Western-blot检测鞘氨醇激酶1及caspase-3蛋白的表达，通过Elisa检测神经酰胺及S1P的含量，采用免疫荧光及Elisa来检测老年斑的沉积及水迷宫来检测小鼠行为学的改变。
结果：干预组和对照组的鞘氨醇激酶1mRNA及蛋白表达存在明显的差异。干预组小鼠老年斑沉积速度加快，且其学习及记忆能力损害明显加重。
结论：siRNA-sphk1的重组腺病毒构建成功,且具有抑制Sphk1蛋白表达的功能,该基因沉默后,促进了APP/PS1双转基因AD模型鼠老年斑的沉积及其学习和记忆能力的损害。
第四部分小分子RNA干扰鞘氨醇激酶1对APP/PS1双转基因AD鼠作用机制的研究
目的：观察腺病毒介导的鞘氨醇激酶1低表达对APP/PS1双转基因AD模型鼠海马区凋亡的影响，进一步明确sphk1低表达对AD模型鼠作用的可能机制。
方法立体定位注射法将携带siRNA-sphk1的腺病毒载体注射至APP/PS1双转基因AD模型鼠海马区,以1X1011pfu/ml的病毒总量分2点注射，对照组海马内注射等量生理盐水，四周后进行检测，观察海马组织凋亡的改变，以及caspase-3表达的改变。
结果：注射Sphk1-siRNA的小鼠30d后海马区与对照组相比，转染后TUNEL果显示凋亡程度显著提高，且western-blot结果显示caspase-3表达显著增多。
结论：上述结果表明, siRNA-sphk1的重组腺病毒成功沉默sphk1基因后,促进了APP/PS1双转基因AD模型鼠海马区的凋亡。
Part I. Overexpression of Sphingosine Kinase-1Rescues TransgenicMouse Model of Alzheimer’s Disease from Neurotoxicity ofAmyloid-β (Aβ) protein
Objective: Aberrant production and accumulation of amyloid-β（Aβ）protein is central tothe pathogenesis of Alzheimer’s disease (AD) and has a causal role in dementia. Evidenceshowed that imbalance of sphingosine1-phosphate (S1P)/ceramide rheostat may be part ofa mechanism. The aim of this study was to explore the effects of overexpression ofsphingosine kinase-1on the APP/PS1transgenic mouse model of Alzheimer’s Disease.
Methods: In this study, APPsw/PS1double-transgenic（APP/PS1）mice were adopted andreceived an intra-hippocampal injection of recombinant adenovirus-mediated vectorstargeting Sphk1gene(rAV-Sphk1) to evaluate the role of sphingosine kinase-1(Sphk1), acritical regulator of the balance between S1P/ceramide rheostat, in the pathologicalprogression of AD. Confocal microscopy was used to evaluate the disposition of amyloidprotein. The protein expression of sphk1were determined by Western blot. Elisa wasdesigned to assess the secretion of amyloid protein. Mirror water maze was used to detectthe damage of behavior of APP/PS1double transgenic mouse model.
Results: Administration of rAV-Sphk1to the APP/PS1mice four weeks later exhibitedoverexpression of Sphk1protein coupled with decreased deposition of Aβ protein followedby improved learning and memory abilities. Conclusions: These results demonstrate that overexpression of Sphk1could efficientlyattenuate the pathological damage of AD. Therefor, Sphk1overexpression mitigated thepathological damage of AD, establishing a critical role of Sphk1overexpression for AD andSphk1gene delivery would be a novel strategy for the treatment of AD.
Part II. The mechanism of the protective effects of sphingosine kinase1on the of APP/PS1double transgenic AD mice
Objective: The first part of the study found that sphingosine kinase1over-expression canreduce the deposition of senile plaques in mice and mitigate the damage of their behavior,but we have not yet to clear the way of Sphk1protective effect. The purpose of this part isto explore the mechanism of the protective effects of sphingosine kinase1on the APP/PS1double transgenic AD mice.
Methods: In this section, Caspase-3protein expression was assessed by Western blot.TUNEL was used to assay the degree of apoptosis. The expression of s1pr1, s1pr3mRNAwere measured by real-time PCR. Enzyme-linked immunosorbent assay (ELISA) designedto evaluate the CER, S1P secretion. Ultrafine electron microscopy to detect thehippocampal ultrastructure of APP/PS1double transgenic mouse.Results: Four weeks after stereotactic injection, the APP/PS1mice showed a decline inceramide/S1P proportion coupled with a lower degree of apoptosis. And Sphk1over-expression could inhibite the caspase-3expression significantly. Elevated S1Pr1expression and postsynaptic membrane SNAP-25protein expression increased synapticactivity.
Conclusion: These findings suggest that overexpression of Sphk1could suppress apoptosisvia the capases-3pathway and up-regulate synaptic activity by SNAP-25and s1p receptor(s1p-GPCRs).
Part III. Effects of Small Interfering RNA Targeting SphingosineKinase-1Gene On The Animal Model Of Alzheimer’s Disease
Objective：Alzheimer’s disease (AD) is an age-related, progressive neurodegenerativedisorder that occurs gradually and results in memory, behavior, and personality changes.Abnormal sphingolipid metabolism was reported in AD previously. And our previous studyshowed that：over-expression of Sphk1could suppress apoptosis and relieve the depositionof Aβ protein,which demonstrated from the good side the protective role of Sphk1in theAPP/PS1double transgenic mouse.The aim of this study was to explore the effects ofdownregulating the expression of Sphk1expression by the way of small interferingRNA(siRNA) on the APP/PS1double transgenic mouse.
Mehtods: An adenovirus vector that expressed small interfering RNA(siRNA)against theSphk1gene（Sphk1-siRNA）was designed, then effects of Sphk1-siRNA on the APP/PS1mouse4weeks after treatment with sphk1-siRNA hippocampcal injection was examined.Sphk1protein expression were confirmed using Western blot and ceramide content coupledwith S1P secretion was evaluated by enzyme-linked immunosorbent assay (Elisa). Aβ loadwas detected by Immunohistochemical staining and ELISA. Morris water maze wasadopted to test the learning and memory ability of the APP/PS1mice.Results: A significant difference in the expression of Sphk1protein and mRNA wasobserved between the siRNA group and the control group. Aβ load in transfected mice wasaccelerated in vivo, with significant aggravation of the learning and memory ability.
Conclusion: The results show that the recombinant adenovirus vector containing thesphk1gene was successfully constructed, which can accelerate the burdern of Aβ load andthe learning and memory ability, silence SPhK1gene in vivo. The Sphk1gene modulationin the in the animal model of AD may be important for the treatment of AD.
Part IV. The mechanism of Small Interfering RNA TargetingSphingosine Kinase-1Gene On Apoptosis of The Animal Model OfAlzheimer’s Disease
Objective To observe the effect of the recombinant adenovirus vector that expressed smallinterfering RNA(siRNA)against the sphk1gene（Sphk1-siRNA）on the apoptosis ofAPP/PS1double transgenic mouse.
Methods After the recombinant adenovirus vector containing the sphk1gene wassuccessfully constructed，then effect of the recombinant adenovirus vector that expressedsmall interfering RNA(siRNA)against the sphk1gene（siRNA-sphk1）on the apoptosis ofAPP/PS1double transgenic mouse30days after treatment with siRNA-sphk1hippocampcal injection was examined.
Results: Compared with the saline group， the apoptosis degree and the caspase-3expression in the siRNA-sphk1group were markedly increased.Conclusions The results show that the recombinant adenovirus vector containing thesphk1gene was successfully constructed, which can increase the apoptosis of hippocampusin vivo.
引文
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[21] Tamboli, I.Y., Prager, K., Barth, E., Heneka, M., Sandhoff, K., Walter, J. Inhibition ofglycosphingolipid biosynthesis reduces secretion of the beta-amyloid precursor protein andamyloid beta-peptide. J. Biol. Chem，2005（280）：28110–28117.
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