慢性脑缺血大鼠海马区Cdc42的表达及认知功能障碍的研究
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摘要
背景和目的
随着长期慢性脑低灌注可致各种中枢神经系统疾病的观点被大量科学实验研究所证实,人们对慢性脑低灌注的关注度逐年增加。其中,慢性脑低灌注与老年人及阿尔兹海默病(AD)患者的认知功能下降存在着紧密联系。AD是一种隐袭发生的、复杂多样的且进行性加重的累计脑内多个区域的致死性神经系统变性疾病,占据各种原因所致痴呆中的最大一部分,其最显著的特征之一即为全面广泛性的认知功能损害。脑灌注量的降低在AD的发病机制中占据重要地位,从轻度认知功能障碍时即出现的这种全脑灌注量的下降可一直存在并持续到AD患者疾病的晚期,可以显著影响中枢神经系统脑组织结构、功能、认知,给患者带来不可逆转的严重损害,其中特别是对于记忆能力的损害尤为严重。脑血流循环异常是大多数神经及精神疾病的诱因,脑内某一区域的突然供血不足可导致梗死的发生,但是长期缓慢的血流减少可导致记忆减退及痴呆的发生进展。脑血流量的减少与痴呆所致认知功能障碍之间的关系已经被明确阐述。目前对于AD尚无明确的治疗方案,改善AD患者长期脑血流低灌注状态可能成为治疗AD的新的靶点。
树突棘数目、形态结构以及突触可塑性对于学习记忆等认知功能的形成及维持至关重要,而Cdc42是目前已知研究最多的调节树突棘及突触生长发生的Rho家族中的重要一员。Cdc42是人体内调控肌动蛋白细胞骨架的重要调节蛋白,对于细胞的分化、迁移、树突棘的生长延伸及形态构成等方面均发挥重要作用。Cdc42的突变、表达量下降或Cdc42通路中任一蛋白的表达异常都会对树突棘的生长产生不良影响,进而对认知功能产生影响。
双侧颈动脉永久结扎术(2VO)作为制备慢性脑低灌注的经典动物模型被广泛应用于血管性痴呆等许多脑血管疾病的研究。大量证据证明2VO术后可导致模型组动物较正常对照组动物的学习记忆等能力明显下降。
故在本实验中,我们选用2VO术处理大鼠以求模拟人脑组织中的慢性脑缺血状态,研究Cdc42在慢性脑缺血状态下大鼠海马组织中的表达变化及其与认知功能障碍之间的关系。
方法
1.SD大鼠40只,随机平均分为4组,每组10只,分别为假手术组、持久性双侧颈总动脉结扎(2VO)8周组、10周组、12周组。
2.采用持久性双侧颈总动脉结扎术处理模型组大鼠,假手术组大鼠除不结扎双侧颈总动脉外其余处理均同模型组大鼠。
3.用Morris水迷宫分别检测各组大鼠的空间学习记忆能力。
4.用免疫组织化学方法检测各组大鼠脑组织海马内Cdc42的表达。
5.用western blot检测各组大鼠脑组织内海马区Cdc42的表达。
6.用SPSS统计软件分析所得数据。
结果
1.Morris水迷宫结果显示手术组大鼠较假手术组大鼠逃避潜伏期明显延长,穿越平台次数明显减少(P<0.05)。
2.免疫组化结果显示手术组大鼠脑组织海马区中Cdc42的阳性细胞百分数明显低于假手术组大鼠(P<0.05)。
3.western blot结果显示手术组大鼠海马区内Cdc42的表达量明显低于假手术组大鼠(P<0.05)。
结论
实验中,发现随慢性脑缺血时间的延长,大鼠海马区Cdc42的表达量也进行性下降,同时可观察到大鼠在Morris水迷宫中的空间学习记忆能力等认知功能障碍进行性加重,提示慢性脑缺血所致认知功能减退与Cdc42之间存在着某种关联。
Background and Object
as the standpoint that long-term chronic cerebral hypo perfusion can lead to kinds of neurodegenerative diseases be confirmed by a great quantity of experimental data, people begin to focus on the chronic cerebral hypo perfusion more and more frequently. chronic cerebral hypo perfusion keep close contact with cognitive deficiencies of aging people and AD patients. AD is an insidious progressive and complex neurodegenerative diseases which can affect multi-regions of central nervous system. AD accounts for the vast majority of dementia, and one of its most striking features is the global cognitive disability. Indeed, vascular factors play a critical role in the pathogenesis of AD. Perfusion deficiencies are present from the very early pre-clinical phases of AD (mild cognitive impairment (MCI)) and persist well into the latest stages of the disease, demonstrating a pattern of increased hypoperfusion with disease development. This phenomenon, over time, yields catastrophic consequences on brain structure, function, and cognition, leaving the patient irreversibly impaired, especially in their memory faculties. Perfusion disorders are considered to be the incentive reason of most mental diseases and neurodegenerative diseases. A sudden decrease of cerebral blood of the special part of brain may lead to infarction occurred, but the long-term hypo perfusion is the vital component of memory loss and the dementia progress. The extract correlation between AD and the cerebral hypo perfusion have already been clarified. AS there is no effective and straightforward treatments especially target to AD have been found so far, ameliorate the cerebral hypo perfusion state may be the new treatment target spot of AD.
The Number and morphology of dendritic spine and synaptic plasticity is very important to the the formation and maintain of normal cognitive which including studying and memory. Vast compelling evidence suggest that Rho-family GTPases play essential roles in orchestrating the development and remodeling of spines and synapses plasticity. and the protein Cdc42 is one of the most important member of the Rho family. Cdc42,a key regulators of the actin cytoskeleton, can play a significant part in regulating physiology activities including cell differentiation migration spine branching and morphology structure. the mutation or low expression of Cdc42 will have negative effects on the outgrowth of dendritic spines and synaptic and then lead to cognitive deficiencies. Also the abnormal of any protein of the Cdc42 pathway will have the same effect as above.
Bilateral permanent carotid artery ligation (2VO) is the most popular method to simulate the state of the chronic cerebral hypo perfusion to study various kinds of central nervous system diseases like Vascular dementia and Alzheimer's disease, masses of studies have already revealed the conclusion that compared to the normal control group animals,the 2VO model group animals have a obvious decrease in the ability of studying and memory.
So, in this experiment, we prepare to handle the rats with the 2VO surgery to imitate the chronic cerebral ischemia state in adult human, and investigate the possible relationship between the expression of cell division cycle 42 GTP-binding protein(Cdc42) and the cognitive deficiencies in the cerebral blood flow deduction state of the rat hippocampus.
Method
1. Forty SD rats were equally divided into 4 groups:Sham operation control group and 2-VO model groups(permanent ligation of bilateral common carotid arteries for 8,10 and 12 weeks, respectively).
2. handle the 2VO model rats with permanent ligation of bilateral common carotid arteries, and handle the sham-operated group as same as the 2VO model groups rats except occlude the bilateral common carotid arteries.
3. use Morris water maze to detect the cognitive function of the rats including learning and memory.
4. The brains were taken at week 8,10 and 12 after the establishment of models for measuring the expression of Cdc42 protein using immunohistochemistry.
5. The brains were taken at week 8,10 and 12 after the establishment of models for measuring the expression of Cdc42 protein using western blotting.
6. The statistical package for the social sciences(SPSS) were used to analyze the data obtaining.
Results
1. In the Morris water maze, the model group rats needed more escape time than the control group, and they did not swim longer in platform quadrant crossing than in the others in the Morris water tests (P<0.05).
2. the Cdc42 positive cells on hippocampal areas in the model rats was significantly deducted than in the control rats(P<0.05).
3. the expression of Cdc42 on hippocampal areas in the model rats was significantly decreased than in the control rats(P<0.05).
Conclusions
as the ischemia state prolong, the cognitive deficiencies of the rats become more and more serious, and at the same time the expression of Cdc42 decrease dramatically this phenomenon may suggest that there are some correlations between Cdc42 and the cognitive deficiencies.
随着长期慢性脑低灌注可致各种中枢神经系统疾病的观点被大量科学实验研究所证实,人们对慢性脑低灌注的关注度逐年增加。其中,慢性脑低灌注与老年人及阿尔兹海默病(AD)患者的认知功能下降存在着紧密联系。AD是一种隐袭发生的、复杂多样的且进行性加重的累计脑内多个区域的致死性神经系统变性疾病,占据各种原因所致痴呆中的最大一部分,其最显著的特征之一即为全面广泛性的认知功能损害。脑灌注量的降低在AD的发病机制中占据重要地位,从轻度认知功能障碍时即出现的这种全脑灌注量的下降可一直存在并持续到AD患者疾病的晚期,可以显著影响中枢神经系统脑组织结构、功能、认知,给患者带来不可逆转的严重损害,其中特别是对于记忆能力的损害尤为严重。脑血流循环异常是大多数神经及精神疾病的诱因,脑内某一区域的突然供血不足可导致梗死的发生,但是长期缓慢的血流减少可导致记忆减退及痴呆的发生进展。脑血流量的减少与痴呆所致认知功能障碍之间的关系已经被明确阐述。目前对于AD尚无明确的治疗方案,改善AD患者长期脑血流低灌注状态可能成为治疗AD的新的靶点。
树突棘数目、形态结构以及突触可塑性对于学习记忆等认知功能的形成及维持至关重要,而Cdc42是目前已知研究最多的调节树突棘及突触生长发生的Rho家族中的重要一员。Cdc42是人体内调控肌动蛋白细胞骨架的重要调节蛋白,对于细胞的分化、迁移、树突棘的生长延伸及形态构成等方面均发挥重要作用。Cdc42的突变、表达量下降或Cdc42通路中任一蛋白的表达异常都会对树突棘的生长产生不良影响,进而对认知功能产生影响。
双侧颈动脉永久结扎术(2VO)作为制备慢性脑低灌注的经典动物模型被广泛应用于血管性痴呆等许多脑血管疾病的研究。大量证据证明2VO术后可导致模型组动物较正常对照组动物的学习记忆等能力明显下降。
故在本实验中,我们选用2VO术处理大鼠以求模拟人脑组织中的慢性脑缺血状态,研究Cdc42在慢性脑缺血状态下大鼠海马组织中的表达变化及其与认知功能障碍之间的关系。
方法
1.SD大鼠40只,随机平均分为4组,每组10只,分别为假手术组、持久性双侧颈总动脉结扎(2VO)8周组、10周组、12周组。
2.采用持久性双侧颈总动脉结扎术处理模型组大鼠,假手术组大鼠除不结扎双侧颈总动脉外其余处理均同模型组大鼠。
3.用Morris水迷宫分别检测各组大鼠的空间学习记忆能力。
4.用免疫组织化学方法检测各组大鼠脑组织海马内Cdc42的表达。
5.用western blot检测各组大鼠脑组织内海马区Cdc42的表达。
6.用SPSS统计软件分析所得数据。
结果
1.Morris水迷宫结果显示手术组大鼠较假手术组大鼠逃避潜伏期明显延长,穿越平台次数明显减少(P<0.05)。
2.免疫组化结果显示手术组大鼠脑组织海马区中Cdc42的阳性细胞百分数明显低于假手术组大鼠(P<0.05)。
3.western blot结果显示手术组大鼠海马区内Cdc42的表达量明显低于假手术组大鼠(P<0.05)。
结论
实验中,发现随慢性脑缺血时间的延长,大鼠海马区Cdc42的表达量也进行性下降,同时可观察到大鼠在Morris水迷宫中的空间学习记忆能力等认知功能障碍进行性加重,提示慢性脑缺血所致认知功能减退与Cdc42之间存在着某种关联。
Background and Object
as the standpoint that long-term chronic cerebral hypo perfusion can lead to kinds of neurodegenerative diseases be confirmed by a great quantity of experimental data, people begin to focus on the chronic cerebral hypo perfusion more and more frequently. chronic cerebral hypo perfusion keep close contact with cognitive deficiencies of aging people and AD patients. AD is an insidious progressive and complex neurodegenerative diseases which can affect multi-regions of central nervous system. AD accounts for the vast majority of dementia, and one of its most striking features is the global cognitive disability. Indeed, vascular factors play a critical role in the pathogenesis of AD. Perfusion deficiencies are present from the very early pre-clinical phases of AD (mild cognitive impairment (MCI)) and persist well into the latest stages of the disease, demonstrating a pattern of increased hypoperfusion with disease development. This phenomenon, over time, yields catastrophic consequences on brain structure, function, and cognition, leaving the patient irreversibly impaired, especially in their memory faculties. Perfusion disorders are considered to be the incentive reason of most mental diseases and neurodegenerative diseases. A sudden decrease of cerebral blood of the special part of brain may lead to infarction occurred, but the long-term hypo perfusion is the vital component of memory loss and the dementia progress. The extract correlation between AD and the cerebral hypo perfusion have already been clarified. AS there is no effective and straightforward treatments especially target to AD have been found so far, ameliorate the cerebral hypo perfusion state may be the new treatment target spot of AD.
The Number and morphology of dendritic spine and synaptic plasticity is very important to the the formation and maintain of normal cognitive which including studying and memory. Vast compelling evidence suggest that Rho-family GTPases play essential roles in orchestrating the development and remodeling of spines and synapses plasticity. and the protein Cdc42 is one of the most important member of the Rho family. Cdc42,a key regulators of the actin cytoskeleton, can play a significant part in regulating physiology activities including cell differentiation migration spine branching and morphology structure. the mutation or low expression of Cdc42 will have negative effects on the outgrowth of dendritic spines and synaptic and then lead to cognitive deficiencies. Also the abnormal of any protein of the Cdc42 pathway will have the same effect as above.
Bilateral permanent carotid artery ligation (2VO) is the most popular method to simulate the state of the chronic cerebral hypo perfusion to study various kinds of central nervous system diseases like Vascular dementia and Alzheimer's disease, masses of studies have already revealed the conclusion that compared to the normal control group animals,the 2VO model group animals have a obvious decrease in the ability of studying and memory.
So, in this experiment, we prepare to handle the rats with the 2VO surgery to imitate the chronic cerebral ischemia state in adult human, and investigate the possible relationship between the expression of cell division cycle 42 GTP-binding protein(Cdc42) and the cognitive deficiencies in the cerebral blood flow deduction state of the rat hippocampus.
Method
1. Forty SD rats were equally divided into 4 groups:Sham operation control group and 2-VO model groups(permanent ligation of bilateral common carotid arteries for 8,10 and 12 weeks, respectively).
2. handle the 2VO model rats with permanent ligation of bilateral common carotid arteries, and handle the sham-operated group as same as the 2VO model groups rats except occlude the bilateral common carotid arteries.
3. use Morris water maze to detect the cognitive function of the rats including learning and memory.
4. The brains were taken at week 8,10 and 12 after the establishment of models for measuring the expression of Cdc42 protein using immunohistochemistry.
5. The brains were taken at week 8,10 and 12 after the establishment of models for measuring the expression of Cdc42 protein using western blotting.
6. The statistical package for the social sciences(SPSS) were used to analyze the data obtaining.
Results
1. In the Morris water maze, the model group rats needed more escape time than the control group, and they did not swim longer in platform quadrant crossing than in the others in the Morris water tests (P<0.05).
2. the Cdc42 positive cells on hippocampal areas in the model rats was significantly deducted than in the control rats(P<0.05).
3. the expression of Cdc42 on hippocampal areas in the model rats was significantly decreased than in the control rats(P<0.05).
Conclusions
as the ischemia state prolong, the cognitive deficiencies of the rats become more and more serious, and at the same time the expression of Cdc42 decrease dramatically this phenomenon may suggest that there are some correlations between Cdc42 and the cognitive deficiencies.
引文
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[14]Van Aelst L, Cline HT. Rho GTPases and activity-dependent dendrite development.Curr Opin Neurobiol 2004; 14:297-304.
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[16]Koh C-G. Rho GTPases and their regulators in neuronal functions and development. Neurosignals 2006; 15:228-237.
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[18]Long H, Zhu X, Yang P,et al.Myo9b and RICS Modulate Dendritic Morphology of Cortical Neurons. Cereb Cortex.2012 Jan 16.
[19]Joberty G, Petersen C, Gao L, et al. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42 [J]. Nat Cell Biol,2000,2(8):531-539.
[20]Jan YN, Jan LY. Polarity in cell division:what frames thy fearful asymmetry [J]. Cell, 2000,100(6):599-602.
[21]Ng J, Nardine T, Harms M, et al. Rac GTPases control axon growth, guidance and branching. Nature,2002,416(6879):442-7.
[22]Hayashi K, Ohshima T, Mikoshiba K. Pakl is involved in dendrite initiation as a downstream effector of Racl in cortical neurons. Mol Cell Neurosci,2002,20(4):579 594.
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[26]Manning G, Plowman G.D. Evolution of protein kinase signaling from yeast to man. Trends Biochem.Sci.2002,27,514-520.
[27]Murai kk, Pasquale EB. Eph receptors,ephrins,and synaptic function.Neuroscientist,2004, 10(4:)304-314.
[28]Henkemeyer M, Itkis OS, Ngo M, et al. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus.J Cell Biol,163 (2003), pp.1313-1326.
[29]Mark Henkemeyer, Olga S, et al.Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus.J Cell Biol.2003 December 22; 163(6):1313-1326.
[30]K K. Murai, L N Nguyen, F Irie, et al. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling.Nat Neurosci,6 (2003), pp.153-160.
[31]KS Christopherson, EM Ullian, CC Stokes, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.Cell,120 (2005), pp.421-433.
[32]Capsoni S, Tiveron C, Vignone D,et al. Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration. Proc Natl Acad Sci U S A.2010 Jul 6;107(27):12299-304.
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[34]R Levi-Montalcini and PU Angeletti. Nerve growth factor. Physiological Reviews, vol.48, no.3, pp.534-569.
[35]S Korsching, G Auburger, R Heumann, et al. Levels of nerve growth factor and its mRNA in the central nervous system of the rat correlate with cholinergic innervation. EMBO Journal, vol.4, no.6, pp.1389-1393.
[36]I Gozes, D T O'Connor, F E Bloom. A possible high molecular weight precursor to vasoactive intestinal polypeptide sequestered into pheochromocytoma chromaffin granules.Regulatory Peptides, vol.6, no.2, pp.111-119.
[37]I B Black. Trophic molecules and evolution of the nervous system. Proceedings of the National Academy of Sciences of the United States of America, vol.83, no.21, pp. 8249-8252.
[38]L Aloe, L Bracci-Laudiero, S Bonini, et al. The expanding role of nerve growth factor: from neurotrophic activity to immunologic diseases," Allergy, vol.52, no.9, pp.883-894.
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[49]Myers JP, Robles E, Ducharme-Smith A,et al. Focal adhesion kinase modulates Cdc42 activity downstream of positive and negative axon guidance cues. J Cell Sci.2012 Mar 5.
[50]Ma L, Greenwood JA, Schachner M. CRP1, a protein localized in filopodia of growth cones, is involved in dendriticgrowth. J Neurosci.2011 Nov 16;31(46):16781-91.
[51]Chiang SH, Hwang J, Legendre M,et al. TCGAP, a multidomain Rho GTPase-activating protein involved in insulin-stimulated glucose transport. EMBO J.2003 Jun 2;22(11): 2679-91.
[52]Liu H, Nakazawa T, Tezuka T, et al.Physical and functional interaction of Fyn tyrosine kinase with a brain-enriched Rho GTPase-activating protein TCGAPJ Biol Chem.2006 Aug 18;281(33):23611-9.
[53]Scott EK, Reuter JE, Luo L.Small GTPase Cdc42 is required for multiple aspects of dendritic morphogenesisJ Neurosci.2003 Apr 15;23(8):3118-23.
[54]Shen PC, Xu DF, Liu JW,et al. TC10 β/CDC42 GTPase activating protein is required for the growth of cortical neuron dendritesNeuroscience.2011 Dec 29;199:589-97.
[55]Irwin SA, Galvez R, Greenough WT. Dendritic spine structural anomalies in fragile-X mental retardation syndromeCereb Cortex.2000 Oct;10(10):1038-44.
[56]Liu H, Nakazawa T, Tezuka T,et al. Physical and functional interaction of Fyn tyrosine kinase with a brain-enriched Rho GTPase-activating protein TCGAP.J Biol Chem.2006 Aug 18;281(33):23611-9.
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