电针对APP转基因鼠脑Aβ水平及脑微血管病变影响的研究
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摘要
阿尔茨海默病(AD)是以记忆力减退、认知功能障碍为特征的渐进性中枢神经系统退行性疾病。由于其发病机制尚不完全明了,迄今也无肯定而有效的治疗措施,其相关研究已成为国内外医学研究的重点课题之一。AD的主要病理特征为脑神经细胞外β淀粉样蛋白(Aβ)沉积所形成的老年斑(SP)、神经细胞内的神经原纤维缠结(NFTs)、神经细胞及突触脱失以及脑血管淀粉样变(CAA)等。Aβ假说是目前公认度最高的AD发病机制学说,该学说认为脑内Aβ聚集及其神经毒性造成其一系列病理变化及临床表现；由于Aβ产生与清除失衡而导致脑内Aβ水平的增高。近年来,针对脑微血管Aβ清除途径的研究已成为探讨AD发病机制、选择治疗靶点的热点。
中医认为AD病位在脑,与肾密切相关；病性属本虚表实,肾精亏虚致髓海不足,脑失充养；痰瘀浊毒阻络,蒙蔽脑窍。针刺可通经络、活气血,“百会、涌泉”配伍既可祛瘀通络化浊、开窍醒神,又可补肾填髓。针刺有可能通过对脑络——脑微血管的结构与功能的调节对脑内Aβ的清除产生影响,降低脑Aβ水平,减少Aβ毒性作用。为此,我们以针刺对脑内Aβ水平、对脑微血管结构及Aβ清除转运受体LRP1等的影响作为研究靶点,探讨揭示针刺治疗AD的相关作用机制。
实验目的：
通过观察脑内Aβ分布部位及水平、脑微血管壁结构变化及Aβ血脑屏障主动转运受体LRP1的表达水平,探索APP转基因鼠脑内Aβ水平升高的机制；同时观察电针对脑内Aβ水平及微血管病理变化的影响,探讨电针能否影响脑内Aβ水平,其机制是否与Aβ血管清除途径有关,为AD“毒阻脑络”理论及针刺“通络祛毒”理论提供实验依据。
实验方法：
本实验以13月龄APP695V717I转基因鼠为AD动物模型,将12只APP转基因鼠随机分入模型组(M)和电针治疗组(EA),每组6只；以6只同龄C57BL／6鼠为正常对照组(C)。电针治疗组针刺“百会”、“涌泉”穴3个月,模型组、正常对照组除不针刺外,其它处理与电针治疗组相同。采用LashleyⅢ水迷宫、Y-电迷宫测试APP转基因鼠的学习记忆行为学变化及电针影响；采用免疫组织化学(IH)、ThioflavinS染色、酶联免疫吸附测定(ELISA)、蛋白质免疫印记分析(WB)、透射电镜(EM)等技术和方法,观察脑内Aβ阳性表达部位及水平、Aβ清除转运受体LRP1阳性表达部位及水平,观察脑微血管Aβ沉积情况、超微结构变化及电针对其影响。
实验结果：
1) LashleyⅢ水迷宫测试结果显示,16月龄APP转基因鼠水迷宫游出时间、进入盲端次数皆多于正常对照组(P<0.05),而电针治疗组水迷宫游出时间、进入盲端次数皆少于模型组(P<0.05)；Y-电迷宫测试显示,16月龄APP转基因鼠达标所需训练次数多于正常对照组(P<0.05),而电针治疗组达标所需训练次数少于模型组(P<0.05)。提示APP转基因鼠存在学习记忆行为学障碍,电针可有效改善APP转基因鼠的学习记忆能力。
2)电镜超微结构(EM)显示,APP转基因鼠大脑皮层神经元出现明显变性,部分神经元颜色转暗,变形、萎缩,胞体及突起出现大量次级溶酶体,溶酶体内有大量囊胞样结构；脑微血管内皮细胞变薄,局部基底膜增厚,轮廓不清,基底膜外可见高电子密度物质,星形胶质细胞足突肿胀,内容物减少；而电针可在一定程度上改善APP转基因鼠的这些超微结构病理变化。
3)免疫组织化学方法(IH)显示,Aβ表达于神经元胞浆及突起,Aβ1-40表达于大部分神经细胞,而Aβ1-42仅表达于部分神经细胞；APP转基因鼠皮层Aβ1-40、Aβ1-42阳性表达积分光密度(IOD)皆强于正常对照组(P<0.05,P<0.01)；而电针治疗组皮层Aβ1-40、Aβ1-42表达弱于模型组(P<0.05,P<0.01)。脑微血管壁仅呈Aβ1-42阳性表达,ThioflavinS染色证实为脑血管淀粉样沉积,APP转基因鼠海马微血管壁Aβ1-42阳性表达强于正常对照组(P<0.01)；电针组海马微血管壁Aβ1-42阳性表达弱于模型组(P<0.05)。免疫组织化学方法还显示,APP转基因鼠皮层及海马微血管Aβ转运受体LRP1阳性表达弱于正常对照组(P<0.01,P<0.01)；电针治疗组皮层及海马微血管LRP1阳性表达强于模型组(P<0.05,P<0.05)。
4)酶联免疫吸附测定(ELISA)显示,APP转基因鼠脑组织Aβ1-42水平高于正常对照组(P<0.01)；电针治疗组脑组织Aβ1-42水平低于模型组(P<0.01)。结合免疫组化结果,提示电针可降低APP转基因鼠皮层Aβ1-40、A p 1-42免疫组化阳性表达,降低海马微血管Aβ1-42免疫组化阳性表达,降低脑内Aβ1-42水平。ELISA检测还显示,电针可降低APP转基因鼠脑脊液、血清Aβ1-42浓度(P<0.01,P<0.01)。
5)蛋白质免疫印记分析(Western Blot)显示,APP转基因鼠脑组织匀浆LRP1水平明显低于正常对照组,而电针治疗组脑组织匀浆LRP1水平高于模型组。结合免疫组化结果,提示电针可增强APP转基因鼠皮层及海马微血管LRP1免疫组化阳性表达,增强APP转基因鼠脑组织匀浆LRP1水平。
结论：
1.脑神经细胞内Aβ产生增加、血管途径Aβ清除功能减退可能是APP转基因鼠脑组织Aβ水平升高、出现学习记忆功能障碍的主要机制。
2.电针可改善APP转基因鼠的学习记忆行为学障碍,其机制可能是通过影响Aβ的产生及清除而降低脑内Aβ水平,从而减轻了其神经毒性作用。
3.电针可能通过影响APP转基因鼠脑神经元紊乱的自我吞噬机制,减少细胞内Aβ的产生；通过提高脑微血管LRP1介导的Aβ血脑屏障主动转运,减少脑微血管壁Aβ的沉积及脑组织Aβ水平。
4.改善脑微血管结构与功能,提高脑微血管Aβ清除能力,减少脑微血管壁Aβ沉积,可能是电针降低脑Aβ水平的主要机制之一。为针刺“通络祛毒”治疗AD提供了实验依据。
本课题首次利用APP转基因鼠研究了针刺治疗AD的机制。我们发现,APP695V717I转基因鼠的脑微血管壁出现了淀粉样沉积,且脑微血管淀粉样沉积早于典型淀粉样斑块的形成,微血管淀粉样沉积的主要成分为Aβ1-42。在国内尚未见报道。
Alzheimer disease (AD) is a progressive cerebral neurodegenerative process with cognition impairment. Its pathogenesis is not so clear and there are not effective therapies for it now. The pathological hallmarks of AD are extracellelar AP containing senile plaques, intracellular neurofibrillary tangles, loss of neurons and synapses, and cerebrovascular amyloidosis. AP hypothesis is the most popular pathogenesis for AD, claiming the AP accumulation and its neurotoxicity result in the pathological changes and clinical symptoms. Cerebral AP level is associated with the Aβproduction and elimination in the brain; imbalance between AP production and elimination will lead to cerebral AP elevation. AP elimination across blood-brain barrier had been a hot topic in the study of AD pathogenesis and therapeutic targets.
In the theory of Chinese medicine, brain and kidney are the most important organs to senile dementia; AD was caused by kidney essence deficiency, which failed to supply the brain, and cerebral collateral blockage due to blood stasis, phlegm and endogenetic toxin. Acupuncture has a good effect on disorders of central nervous system; DU 20 is the point connecting brain directly, and KI 1 is the source point of Kidney meridian; so acupuncture on DU 20 and KI 1 can dredge meridians and collaterals, promote qi and blood circulation, remove blood stasis, tonify kidney and brain, and recover cognitive impairment. Its effect regulating the function and structure of cerebrovasculature (cerebral collaterals) may promote cerebral Aβelimination across BBB, resulting in reduction of cerebral AP level and its neurotoxicity. So, we discuss the mechanism of acupuncture on AD by affecting cerebral Aβlevel, by promoting Aβelimination across BBB.
OBJECTIVE:
To study the mechanism of high cerebral Aβlevel in APP tg mice by investigating the positive site of Aβin cortex and hippocampus, by investigating the positive site of LRP1, the main Aβtransport receptor on BBB. At the same time, investigate the effect of EA on cerebral Aβlevel, on LRP1, on cerebrovascular amyloidosis to discuss the mechanism of reduction of cerebral Aβlevel by EA on APP tg mice, which may support the theory that AD was caused by cerebral collateral blockage, and acupuncture may dredge cerebral collateral, remove endogenetic toxin.
METHOD:
The present experiment assigned randomly APPV695717I transgenic mice (tg mice) aged 13 months to AD model group (M) and Electroacupuncture group (EA), and compared with same aged C57BL/6 mice. EA group were treated with EA on DU20 and KI1 for 3 months. Techniques and methods of immunohistochemistry (IH), ELISA, Western blot, and transmission electron microscopy were applied to study the effect of EA on cerebral Aβlevel, on LRP1, the main Aβtransport receptor on BBB, on ultrastructure of microvessels.
RESULTS:
1. Showed by Lashley III water maze test, APP tg mice experienced longer swimming time and much error times than control group did (P＜0.05); Showed by Y-electric maze test, APP tg mice need much acquiring times than control group did (P<0.05); And EA can ameliorate cognitive impairment of APP tg mice tested by LashleyⅢwater maze (P<0.05) and by Y-electric maze (P<0.05).
2. EA can ameliorate ultrastructure pathologic changes of APP tg mice, such as neuronal degeneration with abundant multivascula and lysosome, endothelium thinning, basement membrane thickening in cerebral microvasculature, and astroglial endfoot swelling.
3. By immunohistochemistry imaging, Aβ1-40/Aβ1-42 immune positive were shown in neuron bodies and synapses, and walls of microvasculature were positive to Aβ1-42 antibody, which confirmed by Thioflavin S staining as microvascular amloidgenesis. Integrated optical densities (IOD) of Aβ1-40/Aβ1-42 in cortex of model group were higher than that in control group (P<0.05, P＜0.01). And IOD of AP 1-42 in hippocampus of model group were also higher than that in control group (P＜0.05). And EA could reduce immune positive expression of Aβ1-40/Aβ1-42 in cortex of APP tg mice (P＜0.05, P＜0.01); EA could reduce immune positive expression of Aβ1-42 in hippocampus microvasculae of APP tg mice (P＜0.05). LRP1 immune positive expressions in cortex and hippocampus microvessels of model group were lower than that in control group (P＜0.01, P＜0.01); And EA could improve LRP1 immune positive expressions in cortex and hippocampus microvessels of APP tg mice (P＜0.05, P＜0.05).
4. ELISA showed that cerebral Aβ1-42 levels of model group were higher than that in control group (P＜0.01), and EA could reduce cerebral Aβ1-42 levels of APP tg mice (P＜0.01). At the same time, EA could reduce AP 1-42 levels in cerebrospinal fluid and plasma of APP tg mice.
5. Western Blot showed that cerebral LRP1 levels of model group were lower than that in control group, and EA could improve cerebral LRP1 levels of APP tg mice tested by WB.
CONCLUSION:
1. High cerebral Aβlevel, result from increased intracellular Aβproduction and decreased AP elimination by microvessels, is the right curse of AD manifesting cognitive impairment.
2. EA could ameliorate cognitive impairment of APP tg mice by its function reducing cerebral Aβlevel.
3. Cerebral Aβproduction may be reduced by EA effect on lysosome autophagy mechanism; cerebral Aβelimination may be improved by EA effect on LRP1 BBB transport mechanism.
4. Acupuncture may affect the structure and function of microvessels, improving AP elimination by microvessels, reducing Aβaccumulation around microvessels, which support the theory that AD was caused by cerebral collateral blockage, and acupuncture may dredge cerebral collateral, remove endogenetic toxin.
It was the first time for APP tg mouse be applied to EA study on AD. And we found that cerebral microvascular amyloidosis existed in APP695V717I tg mice, and it appeared early than typical amyloid plaques did. Main constitute of cerebral microvascular amyloidosis in APP695V717I tg mice was Aβ1-42.
中医认为AD病位在脑,与肾密切相关；病性属本虚表实,肾精亏虚致髓海不足,脑失充养；痰瘀浊毒阻络,蒙蔽脑窍。针刺可通经络、活气血,“百会、涌泉”配伍既可祛瘀通络化浊、开窍醒神,又可补肾填髓。针刺有可能通过对脑络——脑微血管的结构与功能的调节对脑内Aβ的清除产生影响,降低脑Aβ水平,减少Aβ毒性作用。为此,我们以针刺对脑内Aβ水平、对脑微血管结构及Aβ清除转运受体LRP1等的影响作为研究靶点,探讨揭示针刺治疗AD的相关作用机制。
实验目的：
通过观察脑内Aβ分布部位及水平、脑微血管壁结构变化及Aβ血脑屏障主动转运受体LRP1的表达水平,探索APP转基因鼠脑内Aβ水平升高的机制；同时观察电针对脑内Aβ水平及微血管病理变化的影响,探讨电针能否影响脑内Aβ水平,其机制是否与Aβ血管清除途径有关,为AD“毒阻脑络”理论及针刺“通络祛毒”理论提供实验依据。
实验方法：
本实验以13月龄APP695V717I转基因鼠为AD动物模型,将12只APP转基因鼠随机分入模型组(M)和电针治疗组(EA),每组6只；以6只同龄C57BL／6鼠为正常对照组(C)。电针治疗组针刺“百会”、“涌泉”穴3个月,模型组、正常对照组除不针刺外,其它处理与电针治疗组相同。采用LashleyⅢ水迷宫、Y-电迷宫测试APP转基因鼠的学习记忆行为学变化及电针影响；采用免疫组织化学(IH)、ThioflavinS染色、酶联免疫吸附测定(ELISA)、蛋白质免疫印记分析(WB)、透射电镜(EM)等技术和方法,观察脑内Aβ阳性表达部位及水平、Aβ清除转运受体LRP1阳性表达部位及水平,观察脑微血管Aβ沉积情况、超微结构变化及电针对其影响。
实验结果：
1) LashleyⅢ水迷宫测试结果显示,16月龄APP转基因鼠水迷宫游出时间、进入盲端次数皆多于正常对照组(P<0.05),而电针治疗组水迷宫游出时间、进入盲端次数皆少于模型组(P<0.05)；Y-电迷宫测试显示,16月龄APP转基因鼠达标所需训练次数多于正常对照组(P<0.05),而电针治疗组达标所需训练次数少于模型组(P<0.05)。提示APP转基因鼠存在学习记忆行为学障碍,电针可有效改善APP转基因鼠的学习记忆能力。
2)电镜超微结构(EM)显示,APP转基因鼠大脑皮层神经元出现明显变性,部分神经元颜色转暗,变形、萎缩,胞体及突起出现大量次级溶酶体,溶酶体内有大量囊胞样结构；脑微血管内皮细胞变薄,局部基底膜增厚,轮廓不清,基底膜外可见高电子密度物质,星形胶质细胞足突肿胀,内容物减少；而电针可在一定程度上改善APP转基因鼠的这些超微结构病理变化。
3)免疫组织化学方法(IH)显示,Aβ表达于神经元胞浆及突起,Aβ1-40表达于大部分神经细胞,而Aβ1-42仅表达于部分神经细胞；APP转基因鼠皮层Aβ1-40、Aβ1-42阳性表达积分光密度(IOD)皆强于正常对照组(P<0.05,P<0.01)；而电针治疗组皮层Aβ1-40、Aβ1-42表达弱于模型组(P<0.05,P<0.01)。脑微血管壁仅呈Aβ1-42阳性表达,ThioflavinS染色证实为脑血管淀粉样沉积,APP转基因鼠海马微血管壁Aβ1-42阳性表达强于正常对照组(P<0.01)；电针组海马微血管壁Aβ1-42阳性表达弱于模型组(P<0.05)。免疫组织化学方法还显示,APP转基因鼠皮层及海马微血管Aβ转运受体LRP1阳性表达弱于正常对照组(P<0.01,P<0.01)；电针治疗组皮层及海马微血管LRP1阳性表达强于模型组(P<0.05,P<0.05)。
4)酶联免疫吸附测定(ELISA)显示,APP转基因鼠脑组织Aβ1-42水平高于正常对照组(P<0.01)；电针治疗组脑组织Aβ1-42水平低于模型组(P<0.01)。结合免疫组化结果,提示电针可降低APP转基因鼠皮层Aβ1-40、A p 1-42免疫组化阳性表达,降低海马微血管Aβ1-42免疫组化阳性表达,降低脑内Aβ1-42水平。ELISA检测还显示,电针可降低APP转基因鼠脑脊液、血清Aβ1-42浓度(P<0.01,P<0.01)。
5)蛋白质免疫印记分析(Western Blot)显示,APP转基因鼠脑组织匀浆LRP1水平明显低于正常对照组,而电针治疗组脑组织匀浆LRP1水平高于模型组。结合免疫组化结果,提示电针可增强APP转基因鼠皮层及海马微血管LRP1免疫组化阳性表达,增强APP转基因鼠脑组织匀浆LRP1水平。
结论：
1.脑神经细胞内Aβ产生增加、血管途径Aβ清除功能减退可能是APP转基因鼠脑组织Aβ水平升高、出现学习记忆功能障碍的主要机制。
2.电针可改善APP转基因鼠的学习记忆行为学障碍,其机制可能是通过影响Aβ的产生及清除而降低脑内Aβ水平,从而减轻了其神经毒性作用。
3.电针可能通过影响APP转基因鼠脑神经元紊乱的自我吞噬机制,减少细胞内Aβ的产生；通过提高脑微血管LRP1介导的Aβ血脑屏障主动转运,减少脑微血管壁Aβ的沉积及脑组织Aβ水平。
4.改善脑微血管结构与功能,提高脑微血管Aβ清除能力,减少脑微血管壁Aβ沉积,可能是电针降低脑Aβ水平的主要机制之一。为针刺“通络祛毒”治疗AD提供了实验依据。
本课题首次利用APP转基因鼠研究了针刺治疗AD的机制。我们发现,APP695V717I转基因鼠的脑微血管壁出现了淀粉样沉积,且脑微血管淀粉样沉积早于典型淀粉样斑块的形成,微血管淀粉样沉积的主要成分为Aβ1-42。在国内尚未见报道。
Alzheimer disease (AD) is a progressive cerebral neurodegenerative process with cognition impairment. Its pathogenesis is not so clear and there are not effective therapies for it now. The pathological hallmarks of AD are extracellelar AP containing senile plaques, intracellular neurofibrillary tangles, loss of neurons and synapses, and cerebrovascular amyloidosis. AP hypothesis is the most popular pathogenesis for AD, claiming the AP accumulation and its neurotoxicity result in the pathological changes and clinical symptoms. Cerebral AP level is associated with the Aβproduction and elimination in the brain; imbalance between AP production and elimination will lead to cerebral AP elevation. AP elimination across blood-brain barrier had been a hot topic in the study of AD pathogenesis and therapeutic targets.
In the theory of Chinese medicine, brain and kidney are the most important organs to senile dementia; AD was caused by kidney essence deficiency, which failed to supply the brain, and cerebral collateral blockage due to blood stasis, phlegm and endogenetic toxin. Acupuncture has a good effect on disorders of central nervous system; DU 20 is the point connecting brain directly, and KI 1 is the source point of Kidney meridian; so acupuncture on DU 20 and KI 1 can dredge meridians and collaterals, promote qi and blood circulation, remove blood stasis, tonify kidney and brain, and recover cognitive impairment. Its effect regulating the function and structure of cerebrovasculature (cerebral collaterals) may promote cerebral Aβelimination across BBB, resulting in reduction of cerebral AP level and its neurotoxicity. So, we discuss the mechanism of acupuncture on AD by affecting cerebral Aβlevel, by promoting Aβelimination across BBB.
OBJECTIVE:
To study the mechanism of high cerebral Aβlevel in APP tg mice by investigating the positive site of Aβin cortex and hippocampus, by investigating the positive site of LRP1, the main Aβtransport receptor on BBB. At the same time, investigate the effect of EA on cerebral Aβlevel, on LRP1, on cerebrovascular amyloidosis to discuss the mechanism of reduction of cerebral Aβlevel by EA on APP tg mice, which may support the theory that AD was caused by cerebral collateral blockage, and acupuncture may dredge cerebral collateral, remove endogenetic toxin.
METHOD:
The present experiment assigned randomly APPV695717I transgenic mice (tg mice) aged 13 months to AD model group (M) and Electroacupuncture group (EA), and compared with same aged C57BL/6 mice. EA group were treated with EA on DU20 and KI1 for 3 months. Techniques and methods of immunohistochemistry (IH), ELISA, Western blot, and transmission electron microscopy were applied to study the effect of EA on cerebral Aβlevel, on LRP1, the main Aβtransport receptor on BBB, on ultrastructure of microvessels.
RESULTS:
1. Showed by Lashley III water maze test, APP tg mice experienced longer swimming time and much error times than control group did (P＜0.05); Showed by Y-electric maze test, APP tg mice need much acquiring times than control group did (P<0.05); And EA can ameliorate cognitive impairment of APP tg mice tested by LashleyⅢwater maze (P<0.05) and by Y-electric maze (P<0.05).
2. EA can ameliorate ultrastructure pathologic changes of APP tg mice, such as neuronal degeneration with abundant multivascula and lysosome, endothelium thinning, basement membrane thickening in cerebral microvasculature, and astroglial endfoot swelling.
3. By immunohistochemistry imaging, Aβ1-40/Aβ1-42 immune positive were shown in neuron bodies and synapses, and walls of microvasculature were positive to Aβ1-42 antibody, which confirmed by Thioflavin S staining as microvascular amloidgenesis. Integrated optical densities (IOD) of Aβ1-40/Aβ1-42 in cortex of model group were higher than that in control group (P<0.05, P＜0.01). And IOD of AP 1-42 in hippocampus of model group were also higher than that in control group (P＜0.05). And EA could reduce immune positive expression of Aβ1-40/Aβ1-42 in cortex of APP tg mice (P＜0.05, P＜0.01); EA could reduce immune positive expression of Aβ1-42 in hippocampus microvasculae of APP tg mice (P＜0.05). LRP1 immune positive expressions in cortex and hippocampus microvessels of model group were lower than that in control group (P＜0.01, P＜0.01); And EA could improve LRP1 immune positive expressions in cortex and hippocampus microvessels of APP tg mice (P＜0.05, P＜0.05).
4. ELISA showed that cerebral Aβ1-42 levels of model group were higher than that in control group (P＜0.01), and EA could reduce cerebral Aβ1-42 levels of APP tg mice (P＜0.01). At the same time, EA could reduce AP 1-42 levels in cerebrospinal fluid and plasma of APP tg mice.
5. Western Blot showed that cerebral LRP1 levels of model group were lower than that in control group, and EA could improve cerebral LRP1 levels of APP tg mice tested by WB.
CONCLUSION:
1. High cerebral Aβlevel, result from increased intracellular Aβproduction and decreased AP elimination by microvessels, is the right curse of AD manifesting cognitive impairment.
2. EA could ameliorate cognitive impairment of APP tg mice by its function reducing cerebral Aβlevel.
3. Cerebral Aβproduction may be reduced by EA effect on lysosome autophagy mechanism; cerebral Aβelimination may be improved by EA effect on LRP1 BBB transport mechanism.
4. Acupuncture may affect the structure and function of microvessels, improving AP elimination by microvessels, reducing Aβaccumulation around microvessels, which support the theory that AD was caused by cerebral collateral blockage, and acupuncture may dredge cerebral collateral, remove endogenetic toxin.
It was the first time for APP tg mouse be applied to EA study on AD. And we found that cerebral microvascular amyloidosis existed in APP695V717I tg mice, and it appeared early than typical amyloid plaques did. Main constitute of cerebral microvascular amyloidosis in APP695V717I tg mice was Aβ1-42.
引文
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