β淀粉样蛋白对大鼠海马区NADPH氧化酶表达的影响及机制研究
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摘要
背景与目的
阿尔茨海默病(Alzheimer disease,AD)的神经病理学特征是以β-淀粉样蛋白(β-amyloid protein,Aβ)沉积为核心的老年斑(senile plaque,SP)、神经元内神经纤维缠结和继发的炎症反应,其发病机制不清。慢性炎症反应学说越来越引起重视。AD脑内慢性炎症反应的特征包括：Aβ沉积激活小胶质细胞,CDllb为小胶质细胞活化的标志,其活化后分泌炎症介质和炎症细胞因子,其中活性氧(reactive oxygen species,ROS)可直接作用于神经元,引起神经元的退化、凋亡。目前多数学者的研究认为,在Aβ与小胶质细胞相互作用后,引发AD患者神经损伤ROS的主要来源是烟酰胺腺嘌呤二核苷酸磷酸氧化酶(nicotinamide adenine dinucleotide phosphate oxidase,NADPH oxidase)。NADPH氧化酶是一个多聚体跨膜蛋白质,由六种亚基组成,即p47phox、p67phox、p40phox、Rac、p22phox和gp91phox,其中p47phox是该酶的催化亚基,该亚基在海马局部表达增加,提示其活性增强；它的激活可能与非受体型酪氨酸激酶Src家族Fyn、Lyn及酪氨酸激酶Syk有关,PP2可抑制Src激酶的活性。本研究课题通过观察AD模型大鼠海马内Aβ诱导小胶质细胞活化及NADPH氧化酶表达的变化,探讨Aβ1-42引起小胶质细胞NADPH氧化酶活性变化是否依赖Src家族Fyn.Lyn及Syk信号转导通路,为阿尔茨海默病的炎性反应机制及药物治疗靶点提供实验依据。
方法
痴呆动物模型的建立：将Morris水迷宫实验筛选进入试验的72只SD大鼠,随机分为对照组、模型组和PP2干预组,每组24只。模型组每侧海马分别注射Aβ1-42 2.5μl(4μg/μl)；PP2干预组先注射PP2(8μg/rat),1h后于同一位点再注射Aβ1-422.5μl；对照组注射等容积生理盐水。于第10d对各组大鼠进行Morris水迷宫训练,连续训练5d,记录最后3d的成绩。行为学实验结束后,处死大鼠,免疫荧光法检测Aβ沉积,免疫组织化学法检测CD11b的表达,RT-PCR测定海马区NADPH氧化酶主要亚基及Fyn mRNA的表达,Western Blot测定Fyn、Lyn、Syk及p47phox蛋白的表达。统计学方法采用单因素方差分析,P<0.01或P<0.05具有统计学意义。
结果
1海马注射Aβ1-42后14d,模型组大鼠空间学习记忆障碍明显重于对照组(P<0.05)和PP2干预组(P<0.05),差异具有统计学意义。
2免疫荧光显示模型组和PP2干预组大鼠海马内Aβ1-42聚积,对照组未检测到Aβ1-42。
3免疫组化显示于14d时Aβ1-42诱导小胶质细胞成为CD11lb阳性细胞,形态多为阿米巴样,对照组、模型组和PP2干预组CD11b阳性细胞数分别为(100±15)个、(589±25)个和(525±23)个；模型组与对照组相比(P<0.01),差异具有统计学意义。
4 RT-PCR测定显示模型组NADPH氧化酶亚基p47phox、p67phox、p40phox、p22phox、gp91phoxp及Fyn mRNA表达均明显高于对照组(P<0.05)和PP2干预组(P<0.05),差异具有统计学意义；且模型组p47phox mRNA与Fyn mRNA表达变化呈线性正相关(r=0.968,P<0.01)。
5 Western Blot测定显示模型组Fyn、Lyn、Syk及p47phox蛋白表达均明显高于对照组(P<0.05)和PP2干预组(P<0.05),差异具有统计学意义。
结论
1 Aβ1-42大鼠海马内注射可以成功的制做AD动物模型,即Aβ在脑内沉积可以引起大鼠的学习记忆障碍。
2 Aβ在脑内沉积可以引起脑内慢性炎症反应：Aβ1-42增加小胶质细胞NADPH氧化酶表达,并且NADPH氧化酶的激活依赖Fyn、Lyn
Background and Objective
The pathological changes in encephalon with Alzheimer disease(AD) contain senile plaques and neurofibrillary tangles formation and secondary inflammatory reaction. Pathogenesis of AD is not clear. The theory of chronic inflammatory reaction within the brain has been attach more importance to.Inflammatory characteristics of AD include microglias activated byβ-amyloid(Aβ) protein sediment. CD11b is symbol of microglias activaton. Activated microglias secrete inflammatory substances and cellular factors, reactive oxygen species(ROS) among which can directly damage neurons and lead to the neurons degeneration and apoptosis. At present, studies of a lot of scholars show major source of ROS is nicotinamide adenine dinucleotide phosphate oxidase(NADPH oxidase).NADPH oxidase is a polybody protein, composed of p47phox, p67phox, p40phox, Rac, p22phox and gp91phox.P47phox is catalysis radicle of the enzyme, the increase of whose expression indicates that its power boosts up.The activation of NADPH oxidase is associated with non-receptor protein-tyrosine kinase Src family Fyn, Lyn and Syk. PP2 can inhibite Src kinase. The study discusses whether Fyn, Lyn and Syn result in Aβactivation of NADPH oxidase within microglias in hippocampus through observing the activation by Aβinduction of microglias and changed expression of NADPH oxidase. These provide theoretical foundation for elucidating inflammatory reaction mechanism and finding effective medicine to treat AD.
Methods
Seventy-two rats sieved out through Morris water maze experiment were divided randomly into control group, model group and PP2 treating group. AD animal model was established by injected Aβ1-42 into the rat's hippocampus; PP2 was injected into the rat's hippocampus before Aβ1-42 injected into the rat's hippocampus in PP2 treating group; Same volume 0.9% N-S was injected into the rat's hippocampus in control group. Morris water maze was used to detect capacity of study and memory of the 72 rats on 14th day. After the experiment, the rats were executed. Immunofluorescence method detected Aβsediment in hippocampus; Immunohistochemistry method determined the expression of CD11b;RT-PCR was used to measure the expression of mRNA of main radicles of NADPH oxidase and Fyn, Western Blot to detect the expression of protein of p47phox, Fyn, Lyn and Syk in the hippocampus.
Results
1 Damages of study and memory of the rats in model group were more severe than the rats in control group and PP2 treating group. This difference had statistical significance.
2 Aβ1-42 sediment was more prominent in the hippocampus of the rats in model group and PP2 treating group on 14th day, no Aβ1-42 sediment in the hippocampus of the rats in control group.
3 CD11b positive cells by Aβ1-42 induction significantly increased and were activated. the average of CD11b positive cells numbers among control group and model group and PP2 treating group was 100±1,589±25 and 525±23 respectively. This difference(model group vs.control group) had statistical significance.
4 The expression of the mRNA of p47phox, p67phox, p40phox, p22phox, gp91phox and Fyn in the hippocampal area of the rats in model group was prominently more than it in control group(P<0.05)and PP2 treating group(P<0.05).It had statistical significance. The correlation of the expression of the mRNA of Fyn and p47phox was positive in model group(r=0.968, P<0.01).
5 The expression of p47phox, Fyn, Lyn and Syk in the hippocampus of the rats in model group was significantly more than it in control group(P<0.05)and PP2 treating group(P<0.05).
Conclusions
1 we injected Aβ1-42 into the rat's hippocampus in order to found the model of AD. This model is an ideal model of groundwork study in AD.Aβsediment in brains may damage study and memory of rats.
2 Aβdeposit in brains may lead to inflammatory reaction:Aβincreases the expression of NADPH oxidase. The function may depend on signal transduction pathway of Fyn, Lyn and Syk.
阿尔茨海默病(Alzheimer disease,AD)的神经病理学特征是以β-淀粉样蛋白(β-amyloid protein,Aβ)沉积为核心的老年斑(senile plaque,SP)、神经元内神经纤维缠结和继发的炎症反应,其发病机制不清。慢性炎症反应学说越来越引起重视。AD脑内慢性炎症反应的特征包括：Aβ沉积激活小胶质细胞,CDllb为小胶质细胞活化的标志,其活化后分泌炎症介质和炎症细胞因子,其中活性氧(reactive oxygen species,ROS)可直接作用于神经元,引起神经元的退化、凋亡。目前多数学者的研究认为,在Aβ与小胶质细胞相互作用后,引发AD患者神经损伤ROS的主要来源是烟酰胺腺嘌呤二核苷酸磷酸氧化酶(nicotinamide adenine dinucleotide phosphate oxidase,NADPH oxidase)。NADPH氧化酶是一个多聚体跨膜蛋白质,由六种亚基组成,即p47phox、p67phox、p40phox、Rac、p22phox和gp91phox,其中p47phox是该酶的催化亚基,该亚基在海马局部表达增加,提示其活性增强；它的激活可能与非受体型酪氨酸激酶Src家族Fyn、Lyn及酪氨酸激酶Syk有关,PP2可抑制Src激酶的活性。本研究课题通过观察AD模型大鼠海马内Aβ诱导小胶质细胞活化及NADPH氧化酶表达的变化,探讨Aβ1-42引起小胶质细胞NADPH氧化酶活性变化是否依赖Src家族Fyn.Lyn及Syk信号转导通路,为阿尔茨海默病的炎性反应机制及药物治疗靶点提供实验依据。
方法
痴呆动物模型的建立：将Morris水迷宫实验筛选进入试验的72只SD大鼠,随机分为对照组、模型组和PP2干预组,每组24只。模型组每侧海马分别注射Aβ1-42 2.5μl(4μg/μl)；PP2干预组先注射PP2(8μg/rat),1h后于同一位点再注射Aβ1-422.5μl；对照组注射等容积生理盐水。于第10d对各组大鼠进行Morris水迷宫训练,连续训练5d,记录最后3d的成绩。行为学实验结束后,处死大鼠,免疫荧光法检测Aβ沉积,免疫组织化学法检测CD11b的表达,RT-PCR测定海马区NADPH氧化酶主要亚基及Fyn mRNA的表达,Western Blot测定Fyn、Lyn、Syk及p47phox蛋白的表达。统计学方法采用单因素方差分析,P<0.01或P<0.05具有统计学意义。
结果
1海马注射Aβ1-42后14d,模型组大鼠空间学习记忆障碍明显重于对照组(P<0.05)和PP2干预组(P<0.05),差异具有统计学意义。
2免疫荧光显示模型组和PP2干预组大鼠海马内Aβ1-42聚积,对照组未检测到Aβ1-42。
3免疫组化显示于14d时Aβ1-42诱导小胶质细胞成为CD11lb阳性细胞,形态多为阿米巴样,对照组、模型组和PP2干预组CD11b阳性细胞数分别为(100±15)个、(589±25)个和(525±23)个；模型组与对照组相比(P<0.01),差异具有统计学意义。
4 RT-PCR测定显示模型组NADPH氧化酶亚基p47phox、p67phox、p40phox、p22phox、gp91phoxp及Fyn mRNA表达均明显高于对照组(P<0.05)和PP2干预组(P<0.05),差异具有统计学意义；且模型组p47phox mRNA与Fyn mRNA表达变化呈线性正相关(r=0.968,P<0.01)。
5 Western Blot测定显示模型组Fyn、Lyn、Syk及p47phox蛋白表达均明显高于对照组(P<0.05)和PP2干预组(P<0.05),差异具有统计学意义。
结论
1 Aβ1-42大鼠海马内注射可以成功的制做AD动物模型,即Aβ在脑内沉积可以引起大鼠的学习记忆障碍。
2 Aβ在脑内沉积可以引起脑内慢性炎症反应：Aβ1-42增加小胶质细胞NADPH氧化酶表达,并且NADPH氧化酶的激活依赖Fyn、Lyn
Background and Objective
The pathological changes in encephalon with Alzheimer disease(AD) contain senile plaques and neurofibrillary tangles formation and secondary inflammatory reaction. Pathogenesis of AD is not clear. The theory of chronic inflammatory reaction within the brain has been attach more importance to.Inflammatory characteristics of AD include microglias activated byβ-amyloid(Aβ) protein sediment. CD11b is symbol of microglias activaton. Activated microglias secrete inflammatory substances and cellular factors, reactive oxygen species(ROS) among which can directly damage neurons and lead to the neurons degeneration and apoptosis. At present, studies of a lot of scholars show major source of ROS is nicotinamide adenine dinucleotide phosphate oxidase(NADPH oxidase).NADPH oxidase is a polybody protein, composed of p47phox, p67phox, p40phox, Rac, p22phox and gp91phox.P47phox is catalysis radicle of the enzyme, the increase of whose expression indicates that its power boosts up.The activation of NADPH oxidase is associated with non-receptor protein-tyrosine kinase Src family Fyn, Lyn and Syk. PP2 can inhibite Src kinase. The study discusses whether Fyn, Lyn and Syn result in Aβactivation of NADPH oxidase within microglias in hippocampus through observing the activation by Aβinduction of microglias and changed expression of NADPH oxidase. These provide theoretical foundation for elucidating inflammatory reaction mechanism and finding effective medicine to treat AD.
Methods
Seventy-two rats sieved out through Morris water maze experiment were divided randomly into control group, model group and PP2 treating group. AD animal model was established by injected Aβ1-42 into the rat's hippocampus; PP2 was injected into the rat's hippocampus before Aβ1-42 injected into the rat's hippocampus in PP2 treating group; Same volume 0.9% N-S was injected into the rat's hippocampus in control group. Morris water maze was used to detect capacity of study and memory of the 72 rats on 14th day. After the experiment, the rats were executed. Immunofluorescence method detected Aβsediment in hippocampus; Immunohistochemistry method determined the expression of CD11b;RT-PCR was used to measure the expression of mRNA of main radicles of NADPH oxidase and Fyn, Western Blot to detect the expression of protein of p47phox, Fyn, Lyn and Syk in the hippocampus.
Results
1 Damages of study and memory of the rats in model group were more severe than the rats in control group and PP2 treating group. This difference had statistical significance.
2 Aβ1-42 sediment was more prominent in the hippocampus of the rats in model group and PP2 treating group on 14th day, no Aβ1-42 sediment in the hippocampus of the rats in control group.
3 CD11b positive cells by Aβ1-42 induction significantly increased and were activated. the average of CD11b positive cells numbers among control group and model group and PP2 treating group was 100±1,589±25 and 525±23 respectively. This difference(model group vs.control group) had statistical significance.
4 The expression of the mRNA of p47phox, p67phox, p40phox, p22phox, gp91phox and Fyn in the hippocampal area of the rats in model group was prominently more than it in control group(P<0.05)and PP2 treating group(P<0.05).It had statistical significance. The correlation of the expression of the mRNA of Fyn and p47phox was positive in model group(r=0.968, P<0.01).
5 The expression of p47phox, Fyn, Lyn and Syk in the hippocampus of the rats in model group was significantly more than it in control group(P<0.05)and PP2 treating group(P<0.05).
Conclusions
1 we injected Aβ1-42 into the rat's hippocampus in order to found the model of AD. This model is an ideal model of groundwork study in AD.Aβsediment in brains may damage study and memory of rats.
2 Aβdeposit in brains may lead to inflammatory reaction:Aβincreases the expression of NADPH oxidase. The function may depend on signal transduction pathway of Fyn, Lyn and Syk.
引文
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