G蛋白偶联受体激酶5缺陷在早期阿尔茨海默病发病机制中的潜在作用
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摘要
第一部分雌性G蛋白偶联受体激酶5缺陷小鼠出现恶化的阿尔茨海默病样病理改变
背景:现已知道性别在阿尔茨海默病(AD)的发病中是一不容忽视的危险因素,许多研究表明,AD的患病率女性显著高于男性;与男性相比,女性AD患者脑内呈现出更为严重的病理变化。最近研究揭示G蛋白偶联受体(GPCRs)激酶(5GRK5)缺陷引起的相关GPCRs脱敏障碍在早期AD的病理发生机制中具有重要作用,而且GRK5敲除/缺陷(GRK5KO)小鼠表现出早期AD病理特征和短时期记忆功能损害。但是这种病理变化在不同性别间有没有差异,目前不得而知。目的:研究GRK5KO小鼠出现的AD样病理变化是否存在性别差异,并探讨其分子机制。方法:用Campbell-Switzer银染和免疫荧光染色来观察老化的GRK5KO小鼠海马内肿胀轴突的病理变化;Western blotting检测海马内突触蛋白水平的变化;同时对上述改变在不同性别间进行深入比较。此外,用免疫酶联吸附试验检测黄体生成素(LH)诱导的环磷酸腺苷的聚积量。结果:雌性GRK5KO小鼠海马内呈簇状分布的肿胀轴突数目比雄性小鼠高出2.5倍;而且雌性GRK5KO小鼠海马内数个突触蛋白水平(包括突触素)比雄性小鼠显著减低。双因素方差分析显示性别和GRK5缺陷双因素之间呈显著协同效应,共同促进了雌性GRK5KO小鼠轴突缺陷和部分突触蛋白水平的降低。另外,LH活性增加据认为是引起AD性别差异现象的重要原因,但在本实验中LH受体脱敏并不受GRK5缺陷的影响。由此可见,雌性GRK5KO小鼠出现恶化的病理改变并不是由于LH受体脱敏损害造成的。结论:在促进雌性GRK5KO小鼠出现早期AD样病理改变的过程中,GRK5缺陷和性别双因素表现出协同效应,尽管目前其潜在的分子机制尚未阐明。
第二部分G蛋白偶联受体激酶5缺陷对Tg2576小鼠脑内炎症反应的影响
背景:最近的研究显示功能性(膜上)G蛋白偶联受体激酶5(GRK5)缺陷与早期阿尔茨海默病(AD)的病理发生机制存在联系。体外试验表明,GRK5缺陷通过损害相关G蛋白偶联受体(GPCRs)脱敏可以促进小胶质细胞的激活。但令人遗憾的是,GRK5敲除/缺陷小鼠(GRK5KO)除了有中等程度的轴突缺陷和突触退变以及轻度水平的β淀粉样肽(Aβ)水平上升外,并没有发现纤丝状Aβ沉积,也没有表现出任何小胶质细胞增生迹象。一种可能的解释是体内GRK5缺陷导致的功能缺失有可能被其他的GRK成员所代偿;另外一种原因在于缺少炎症启动因子,诸如纤丝状Aβ。目的:研究在纤丝状Aβ存在时,GRK5缺陷是否会加剧转瑞典突变淀粉样肽前体蛋白基因(TgAPPsw, Tg2576)小鼠脑内的炎症反应,并探讨其作用机制。方法:将具有C57/BL6遗传背景的GRK5KO杂合子与具有相同遗传背景的Tg2576小鼠杂交,以产生野生型(WT)、GRK5KO杂合子型、转淀粉样肽前体蛋白(APP)基因型以及转基因&敲除(Double)型4种基因型小鼠。用定性和定量免疫荧光(IF)染色方法来评价这些动物脑内小胶质和星形胶质细胞的增生反应。用IF染色和Western blotting分别检测脑内Aβ沉积量和水平的变化。结果:抗CD45、CD11b、OX42和白介素1β特异性抗体的IF染色可以特征化小胶质细胞的变化。IF染色结果定量分析显示,Tg2576小鼠被灭活一个拷贝的GRK5基因后导致海马和皮层内小胶质细胞数量和Aβ沉积量(包括负荷量与数量)同时上升了近1倍左右,并伴有星形胶质细胞的显著增生。而且激活的小胶质和星形胶质细胞大多位于或环绕于纤丝状Aβ斑块附近。但IF染色未发现WT和GRK5KO小鼠脑内有明显胶质细胞增生改变,也没有纤丝状Aβ沉积。此外,Aβ的Western blotting检测结果与IF染色相互印证。Spearman等级相关检验发现APP和Double小鼠海马和皮层内Aβ沉积量(负荷量/数量)与对应的小胶质细胞/星形胶质细胞数量均呈高度显著正相关。结论:Tg2576小鼠GRK5基因敲除50%后,确实加剧了脑内的炎症反应,但其加剧的方式不是直接对炎症调节因子加以调控,而主要是通过增强对炎症启动因子(纤丝状Aβ)的调节来发挥作用的。
第三部分G蛋白偶联受体激酶5缺陷对Tg2576小鼠脑内β淀粉样肽前体蛋白加工过程的影响
目的:研究体内G蛋白偶联受体(GPCRs)激酶5(GRK5)缺陷加剧转瑞典突变淀粉样肽前体蛋白(TgAPPsw, Tg2576)基因小鼠脑内纤丝状β淀粉样肽(Aβ)沉积的分子机制。方法:将具有C57/BL6遗传背景的GRK5敲除/缺陷小鼠(GRK5KO)杂合子与具有相同遗传背景的Tg2576小鼠杂交以建立APP (hAPPsw+/-/GRK5+/+)型及转基因&敲除(Double, hAPPsw+/-/GRK5 +/- )型小鼠。用Western blotting检测APP和Double型6月龄雌性小鼠脑内以及17天龄胎鼠皮层原代培养神经元胞膜上全长APP(flAPP)和可溶性APPα(sAPPα)的变化。结果:APP与Double型的6月龄小鼠脑内flAPP水平无差异,但Double小鼠sAPPα水平较APP小鼠明显减低;胎鼠皮层原代培养神经元胞膜上flAPP水平及sAPPα基础释放量的变化与6月龄小鼠类似,但经用乙酰胆碱毒蕈碱样受体(M)2特异性拮抗剂处理后,可以显著逆转Double胎鼠皮层原代培养神经元sAPPα释放量减低的现象。结论:体内GRK5缺陷引起M2受体脱敏障碍,可以通过调节APP的加工过程来加速Double小鼠脑内Aβ的生成。
Part 1 Worsened Alzheimer-like pathology in female GRK5 deficient mice
background: Recent studies suggested that G protein-coupled receptor kinase 5 (GRK5) deficiency plays a significant role in early Alzheimer's disease (AD) pathogenesis, and that GRK5 knockout/deficiency (GRK5KO) mouse displays an early Alzheimer-like cognitive deficit associated with increased hippocampal axonal defects and synaptic degenerative changes. Gender is known to play a role in AD, with female showing more extensive pathologic changes in brain as compared to male. Although GRK5 deficiency is linked to AD, it is unknown whether the pathologic changes solely driven by the GRK5 deficiency are gender-differential. Objective(s): The objective of this study is to determine whether the Alzheimer-like pathologic changes solely driven by the GRK5 deficiency are gender-differential and the potential molecular mechanism. Methods: Campbell-Switzer silver staining and immunofluorescent (IF) staining methods were used to observe the pathology in the hippocampus. Western blotting was used to determine the hippocampal levels of synaptic proteins. The extent of the pathologic changes in aged GRK5KO mice was compared between genders. Results: It was found that the female GRK5KO mice had a 2.5-fold increase in hippocampal swollen axonal clusters compared to male GRK5KO mice. Moreover, hippocampal levels of several synaptic proteins, including synaptophysin, were significantly lower in the female than the male. In addition, although increased Luteinizing hormone (LH) activity is believed to play a significant role in the gender phenomenon in AD, the results in our experiment showed that desensitization of LH receptor was not affected by the GRK5 deficiency. Therefore, the worsened pathologic changes in the female mice cannot be attributed to an impaired LH receptor desensitization. Conclusions: Taken together, this study demonstrates a synergistic interaction between GRK5 deficiency and gender in promoting early AD-like pathologic changes in the female GRK5KO mice, although the underlying molecular mechanisms remain to be elucidated.
Part 2 GRK5 deficiency exaggerates inflammatory changes in Tg2576 mice
Background: Deficiency of membrane G-protein coupled receptor (GPCR) kinase-5 (GRK5) has been recently linked to early AD pathogenesis, and has been suggested to contribute to augmented microglial activation in vitro by sensitizing relevant GPCRs. Although the GRK5 deficiency indeed caused moderate increase in axonal defects and synaptic degenerative changes and a mild increase ofβ-amyloid (Aβ) level, no fibrillar Aβdeposits or any significant signs of microglial activation were observed in the GRK5 knockout/deficiency (GRK5KO) mice. One possible reason for the absence of microgliosis in these animals we proposed previously is that deficiency of GRK5 in vivo may be largely compensated by other GRK members; another reason might be due to lack of inflammatory initiators, such as fibrillar Aβ, because that GRK only acts when GPCR is activated. Objective(s): The objective of this study was to determine whether the microgliosis is exaggerated in TgAPPsw (Tg2576) mice deficient in GRK5, in which fibrillarβ-amyloid (Aβ) and an active inflammatory process involving activated GPCR signaling are present, and to investigate the potential mechanism why inflammation is exaggerated. Methods: The heterozygotes of GRK5KO mice with a C57/BL6 background were bred with Tg2576 mice also with a C57/BL6 background to produce wild type (WT), GRK5KO, amyloid precursor protein (APP) and the double mice for this study. Both quantitative and qualitative immunofluorescent (IF) staining methods were used to evaluate the microgliosis and astrogliosis in these animals. Qualitative IF staining and Western blotting were used to evaluate the changes of Aβin these animals. Results: Inactivation of one copy of the GRK5 gene in the TgAPPsw mice resulted in approximately doubled extent of microgliosis and Aβplaque deposits (including Aβburden and number), along with significantly exaggerated astrogliosis, in both hippocampus and cortex of the aged animals. Consistent with previous observations, the activated microglia and astrocytes were located primarily near or surrounding the fibrillar Aβdeposits. However, IF staining revealed no significant increase of the gliosis and fibrillar Aβdeposits in hippocampus or cortex of WT or GRK5KO mice. The determination of Aβby Western Blotting was consistent with the result of IF staining. Spearman correlation analyses showed a highly significantly positive correlation between fibrillar Aβplaque burden/number and microglia/astrocyte number respectively. Conclusions: The results demonstrate that knockdown GRK5 gene by 50% in the Tg2576 mice significantly exaggerates inflammatory reaction and Aβdeposits in the brain of these animals. The reason why GRK5 deficiency exaggerates inflammatory changes in TgAPPsw mice is unlikely that GRK5 deficiency mediate inflammatory regulators but inflammatory initiators (fibrillar Aβ).
Part3 GRK5 deficiency acceleratesβ-amyloidogenesis in Tg2576 mice by enhancing amyloid precursor protein processing
Objective: The objective of this study was to investigate the molecular mechanisms that the membrane G-protein coupled receptor (GPCRs) kinase-5 (GRK5) deficiency in vivo acceleratesβ-amyloid peptide (Aβ) deposition in TgAPPsw (Tg2576) mice. Methods: The heterozygotes of GRK5/deficient mice (GRK5KO) with a C57/BL6 background were bred with TgAPPsw (Tg2576) mice also with a C57/BL6 background to produce amyloid precursor protein (APP, APPsw+/-/GRK5+/+), and the double (APPsw+/-/GRK5+/-) mice for this study. The soluble APP alpha (sAPPα) and full length APP (flAPP) were observed in 6-month-old female APP and Double mice and the primary culture cortical neuron of 17-day-old APP and Double embryo mice. Results: The results revealed a significant decrease of sAPPαin cortex of the 6-month-old female Double mice as compared to APP mice (p<0.05). But the flAPP levels in the cortex were not significantly different between APP and Double mice. The changes of sAPPαand flAPP in primary culture cortical neuron of 17-day-old APP and Double embryo mice were consistent with the results in 6-month-old APP and Double mice. However, specific antagonist against acetylcholine muscarinic receptor 2 (M2) can remarkably reverse the decrease of sAPPαin primary culture cortical neuron of 17-day-old Double embryo mice. Conclusions: The lack of membrane (functional) GRK5 in vivo results in an impaired M2 receptor desensitization and acceleratesβ-amyloidogenesis in Tg2576 mice by enhancing the APP processing.
背景:现已知道性别在阿尔茨海默病(AD)的发病中是一不容忽视的危险因素,许多研究表明,AD的患病率女性显著高于男性;与男性相比,女性AD患者脑内呈现出更为严重的病理变化。最近研究揭示G蛋白偶联受体(GPCRs)激酶(5GRK5)缺陷引起的相关GPCRs脱敏障碍在早期AD的病理发生机制中具有重要作用,而且GRK5敲除/缺陷(GRK5KO)小鼠表现出早期AD病理特征和短时期记忆功能损害。但是这种病理变化在不同性别间有没有差异,目前不得而知。目的:研究GRK5KO小鼠出现的AD样病理变化是否存在性别差异,并探讨其分子机制。方法:用Campbell-Switzer银染和免疫荧光染色来观察老化的GRK5KO小鼠海马内肿胀轴突的病理变化;Western blotting检测海马内突触蛋白水平的变化;同时对上述改变在不同性别间进行深入比较。此外,用免疫酶联吸附试验检测黄体生成素(LH)诱导的环磷酸腺苷的聚积量。结果:雌性GRK5KO小鼠海马内呈簇状分布的肿胀轴突数目比雄性小鼠高出2.5倍;而且雌性GRK5KO小鼠海马内数个突触蛋白水平(包括突触素)比雄性小鼠显著减低。双因素方差分析显示性别和GRK5缺陷双因素之间呈显著协同效应,共同促进了雌性GRK5KO小鼠轴突缺陷和部分突触蛋白水平的降低。另外,LH活性增加据认为是引起AD性别差异现象的重要原因,但在本实验中LH受体脱敏并不受GRK5缺陷的影响。由此可见,雌性GRK5KO小鼠出现恶化的病理改变并不是由于LH受体脱敏损害造成的。结论:在促进雌性GRK5KO小鼠出现早期AD样病理改变的过程中,GRK5缺陷和性别双因素表现出协同效应,尽管目前其潜在的分子机制尚未阐明。
第二部分G蛋白偶联受体激酶5缺陷对Tg2576小鼠脑内炎症反应的影响
背景:最近的研究显示功能性(膜上)G蛋白偶联受体激酶5(GRK5)缺陷与早期阿尔茨海默病(AD)的病理发生机制存在联系。体外试验表明,GRK5缺陷通过损害相关G蛋白偶联受体(GPCRs)脱敏可以促进小胶质细胞的激活。但令人遗憾的是,GRK5敲除/缺陷小鼠(GRK5KO)除了有中等程度的轴突缺陷和突触退变以及轻度水平的β淀粉样肽(Aβ)水平上升外,并没有发现纤丝状Aβ沉积,也没有表现出任何小胶质细胞增生迹象。一种可能的解释是体内GRK5缺陷导致的功能缺失有可能被其他的GRK成员所代偿;另外一种原因在于缺少炎症启动因子,诸如纤丝状Aβ。目的:研究在纤丝状Aβ存在时,GRK5缺陷是否会加剧转瑞典突变淀粉样肽前体蛋白基因(TgAPPsw, Tg2576)小鼠脑内的炎症反应,并探讨其作用机制。方法:将具有C57/BL6遗传背景的GRK5KO杂合子与具有相同遗传背景的Tg2576小鼠杂交,以产生野生型(WT)、GRK5KO杂合子型、转淀粉样肽前体蛋白(APP)基因型以及转基因&敲除(Double)型4种基因型小鼠。用定性和定量免疫荧光(IF)染色方法来评价这些动物脑内小胶质和星形胶质细胞的增生反应。用IF染色和Western blotting分别检测脑内Aβ沉积量和水平的变化。结果:抗CD45、CD11b、OX42和白介素1β特异性抗体的IF染色可以特征化小胶质细胞的变化。IF染色结果定量分析显示,Tg2576小鼠被灭活一个拷贝的GRK5基因后导致海马和皮层内小胶质细胞数量和Aβ沉积量(包括负荷量与数量)同时上升了近1倍左右,并伴有星形胶质细胞的显著增生。而且激活的小胶质和星形胶质细胞大多位于或环绕于纤丝状Aβ斑块附近。但IF染色未发现WT和GRK5KO小鼠脑内有明显胶质细胞增生改变,也没有纤丝状Aβ沉积。此外,Aβ的Western blotting检测结果与IF染色相互印证。Spearman等级相关检验发现APP和Double小鼠海马和皮层内Aβ沉积量(负荷量/数量)与对应的小胶质细胞/星形胶质细胞数量均呈高度显著正相关。结论:Tg2576小鼠GRK5基因敲除50%后,确实加剧了脑内的炎症反应,但其加剧的方式不是直接对炎症调节因子加以调控,而主要是通过增强对炎症启动因子(纤丝状Aβ)的调节来发挥作用的。
第三部分G蛋白偶联受体激酶5缺陷对Tg2576小鼠脑内β淀粉样肽前体蛋白加工过程的影响
目的:研究体内G蛋白偶联受体(GPCRs)激酶5(GRK5)缺陷加剧转瑞典突变淀粉样肽前体蛋白(TgAPPsw, Tg2576)基因小鼠脑内纤丝状β淀粉样肽(Aβ)沉积的分子机制。方法:将具有C57/BL6遗传背景的GRK5敲除/缺陷小鼠(GRK5KO)杂合子与具有相同遗传背景的Tg2576小鼠杂交以建立APP (hAPPsw+/-/GRK5+/+)型及转基因&敲除(Double, hAPPsw+/-/GRK5 +/- )型小鼠。用Western blotting检测APP和Double型6月龄雌性小鼠脑内以及17天龄胎鼠皮层原代培养神经元胞膜上全长APP(flAPP)和可溶性APPα(sAPPα)的变化。结果:APP与Double型的6月龄小鼠脑内flAPP水平无差异,但Double小鼠sAPPα水平较APP小鼠明显减低;胎鼠皮层原代培养神经元胞膜上flAPP水平及sAPPα基础释放量的变化与6月龄小鼠类似,但经用乙酰胆碱毒蕈碱样受体(M)2特异性拮抗剂处理后,可以显著逆转Double胎鼠皮层原代培养神经元sAPPα释放量减低的现象。结论:体内GRK5缺陷引起M2受体脱敏障碍,可以通过调节APP的加工过程来加速Double小鼠脑内Aβ的生成。
Part 1 Worsened Alzheimer-like pathology in female GRK5 deficient mice
background: Recent studies suggested that G protein-coupled receptor kinase 5 (GRK5) deficiency plays a significant role in early Alzheimer's disease (AD) pathogenesis, and that GRK5 knockout/deficiency (GRK5KO) mouse displays an early Alzheimer-like cognitive deficit associated with increased hippocampal axonal defects and synaptic degenerative changes. Gender is known to play a role in AD, with female showing more extensive pathologic changes in brain as compared to male. Although GRK5 deficiency is linked to AD, it is unknown whether the pathologic changes solely driven by the GRK5 deficiency are gender-differential. Objective(s): The objective of this study is to determine whether the Alzheimer-like pathologic changes solely driven by the GRK5 deficiency are gender-differential and the potential molecular mechanism. Methods: Campbell-Switzer silver staining and immunofluorescent (IF) staining methods were used to observe the pathology in the hippocampus. Western blotting was used to determine the hippocampal levels of synaptic proteins. The extent of the pathologic changes in aged GRK5KO mice was compared between genders. Results: It was found that the female GRK5KO mice had a 2.5-fold increase in hippocampal swollen axonal clusters compared to male GRK5KO mice. Moreover, hippocampal levels of several synaptic proteins, including synaptophysin, were significantly lower in the female than the male. In addition, although increased Luteinizing hormone (LH) activity is believed to play a significant role in the gender phenomenon in AD, the results in our experiment showed that desensitization of LH receptor was not affected by the GRK5 deficiency. Therefore, the worsened pathologic changes in the female mice cannot be attributed to an impaired LH receptor desensitization. Conclusions: Taken together, this study demonstrates a synergistic interaction between GRK5 deficiency and gender in promoting early AD-like pathologic changes in the female GRK5KO mice, although the underlying molecular mechanisms remain to be elucidated.
Part 2 GRK5 deficiency exaggerates inflammatory changes in Tg2576 mice
Background: Deficiency of membrane G-protein coupled receptor (GPCR) kinase-5 (GRK5) has been recently linked to early AD pathogenesis, and has been suggested to contribute to augmented microglial activation in vitro by sensitizing relevant GPCRs. Although the GRK5 deficiency indeed caused moderate increase in axonal defects and synaptic degenerative changes and a mild increase ofβ-amyloid (Aβ) level, no fibrillar Aβdeposits or any significant signs of microglial activation were observed in the GRK5 knockout/deficiency (GRK5KO) mice. One possible reason for the absence of microgliosis in these animals we proposed previously is that deficiency of GRK5 in vivo may be largely compensated by other GRK members; another reason might be due to lack of inflammatory initiators, such as fibrillar Aβ, because that GRK only acts when GPCR is activated. Objective(s): The objective of this study was to determine whether the microgliosis is exaggerated in TgAPPsw (Tg2576) mice deficient in GRK5, in which fibrillarβ-amyloid (Aβ) and an active inflammatory process involving activated GPCR signaling are present, and to investigate the potential mechanism why inflammation is exaggerated. Methods: The heterozygotes of GRK5KO mice with a C57/BL6 background were bred with Tg2576 mice also with a C57/BL6 background to produce wild type (WT), GRK5KO, amyloid precursor protein (APP) and the double mice for this study. Both quantitative and qualitative immunofluorescent (IF) staining methods were used to evaluate the microgliosis and astrogliosis in these animals. Qualitative IF staining and Western blotting were used to evaluate the changes of Aβin these animals. Results: Inactivation of one copy of the GRK5 gene in the TgAPPsw mice resulted in approximately doubled extent of microgliosis and Aβplaque deposits (including Aβburden and number), along with significantly exaggerated astrogliosis, in both hippocampus and cortex of the aged animals. Consistent with previous observations, the activated microglia and astrocytes were located primarily near or surrounding the fibrillar Aβdeposits. However, IF staining revealed no significant increase of the gliosis and fibrillar Aβdeposits in hippocampus or cortex of WT or GRK5KO mice. The determination of Aβby Western Blotting was consistent with the result of IF staining. Spearman correlation analyses showed a highly significantly positive correlation between fibrillar Aβplaque burden/number and microglia/astrocyte number respectively. Conclusions: The results demonstrate that knockdown GRK5 gene by 50% in the Tg2576 mice significantly exaggerates inflammatory reaction and Aβdeposits in the brain of these animals. The reason why GRK5 deficiency exaggerates inflammatory changes in TgAPPsw mice is unlikely that GRK5 deficiency mediate inflammatory regulators but inflammatory initiators (fibrillar Aβ).
Part3 GRK5 deficiency acceleratesβ-amyloidogenesis in Tg2576 mice by enhancing amyloid precursor protein processing
Objective: The objective of this study was to investigate the molecular mechanisms that the membrane G-protein coupled receptor (GPCRs) kinase-5 (GRK5) deficiency in vivo acceleratesβ-amyloid peptide (Aβ) deposition in TgAPPsw (Tg2576) mice. Methods: The heterozygotes of GRK5/deficient mice (GRK5KO) with a C57/BL6 background were bred with TgAPPsw (Tg2576) mice also with a C57/BL6 background to produce amyloid precursor protein (APP, APPsw+/-/GRK5+/+), and the double (APPsw+/-/GRK5+/-) mice for this study. The soluble APP alpha (sAPPα) and full length APP (flAPP) were observed in 6-month-old female APP and Double mice and the primary culture cortical neuron of 17-day-old APP and Double embryo mice. Results: The results revealed a significant decrease of sAPPαin cortex of the 6-month-old female Double mice as compared to APP mice (p<0.05). But the flAPP levels in the cortex were not significantly different between APP and Double mice. The changes of sAPPαand flAPP in primary culture cortical neuron of 17-day-old APP and Double embryo mice were consistent with the results in 6-month-old APP and Double mice. However, specific antagonist against acetylcholine muscarinic receptor 2 (M2) can remarkably reverse the decrease of sAPPαin primary culture cortical neuron of 17-day-old Double embryo mice. Conclusions: The lack of membrane (functional) GRK5 in vivo results in an impaired M2 receptor desensitization and acceleratesβ-amyloidogenesis in Tg2576 mice by enhancing the APP processing.
引文
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