代谢损伤与胰岛素信号通路在阿尔茨海默病发病中的机制研究
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摘要
阿尔茨海默病的非转基因鼠模型（icv-STZ鼠）：与转基因鼠模型（3xTg-AD鼠）的异同点
背景阿尔茨海默病（Alzheimer’s Disease, AD）可以被分为散发性AD和家族性AD。绝大多数AD病例是散发性的，其发病原因非常多元化，包括环境因素，基因和代谢功能等，而家族性AD主要是由于早老素（presenilin，PS）或者是β淀粉样蛋白前体蛋白（amyloid-β precursor protein, APP）基因突变所致。目前，使用非常广泛的一个FAD动物模型是3xTg-AD转基因鼠。这种小鼠具有突变的人PS1， APP, tau基因。但是这个领域仍需要建立针对不同AD发病机制的的动物模型。只有这样，各种可能的治疗AD的药物才能在合适的动物模型上进行临床前期研究。
方法经侧脑室注射链脲霉素(streptozocin，STZ)，建立SAD小鼠模型(icv-STZ小鼠)。在本研究中，我们比较了icv-STZ小鼠与3xTg-AD小鼠在情感，认知行为学，生化以及免疫组化上的异同点。
结果我们发现，两种模型小鼠都存在探索行为活跃，学习及记忆障碍。两种模型小鼠脑内都存在着神经炎性反应，突触蛋白的改变，胰岛素通路的异常，以及高度磷酸化的tau。但是，在icv-STZ小鼠脑内，神经炎性反应更加明显，而在3xTg-AD小鼠脑内，高度磷酸化的tau尤为显著。
结论这些发现证实了icv-STZ小鼠与3xTg-AD小鼠在行为学和神经病理上的异同点。将为AD药物的研发在选择动物模型上提供指导。
散发性(icv-STZ小鼠)与家族性(3xTg-AD小鼠)阿尔茨海默病小鼠模型脑内AD相关基因的比较
研究背景阿尔茨海默病（Alzheimer’s Disease, AD）可以被分为散发性AD（Sporadic AD, SAD）以及家族性AD（Familial AD, FAD）。绝大多数的AD病例都是散发性的，其发病原因可能是多病因的，包括环境，基因和代谢因素。而FAD主要是由于早老素（Presenilin, PS）和β淀粉样前体蛋白(amyloid-β precursorprotein, APP)基因的突变所致。目前，使用非常广泛的一个FAD动物模型是3xTg-AD转基因鼠。这种小鼠具有突变的人PS1， APP, tau基因。而另外还有一种非转基因动物模型，即经侧脑室给予注射链脲霉素(streptozocin，STZ)，建立的模型(icv-STZ小鼠)具有SAD的很多特征，得到了越来越多的关注。尽管这两种模型目前都得到了广泛的关注和应用，其在基因表达上的异同点，仍未有研究。
方法我们通过定量PCR比较了icv-STZ小鼠与3xTg-AD小鼠在海马以及皮层的84个AD相关基因的表达情况。这些基因涉及APP的处理，tau/细胞骨架蛋白，突触功能，凋亡以，自噬，AD相关激酶，糖代谢，胰岛素通路以及mTOR通路。
结果我们发现，在以上所列的范围内，两种模型各有大约有20来个基因的表达发生了改变。很多基因的改变与已经被报道的在AD大脑内的改变一致。海马绝大多数有变化的基因为下调，这两种小鼠模型皮层的基因表达改变差异性更大，在3xTg-AD小鼠内，与突触相关的基因改变较多，而在icv-STZ小鼠内，与胰岛素通路以及糖代谢相关的基因下调更明显。
结论我们的研究证实了icv-STZ小鼠与3xTg-AD小鼠在AD相关基因表达上的异同点，并提供了非常详细的资料。此项研究也为将来基于此两种小鼠模型而进行的AD药物研究提供参考与指导。
经侧脑室注射链脲霉素进一步加重了3xTg-AD小鼠的认知功能障碍以及其他脑功能异常
目的研究代谢异常在AD疾病发生发展中的作用
方法我们将链脲霉素(streptozocin，STZ)（一种经腹腔注射可以诱导动物糖尿病的药物）注射到6个月龄的3xTg-AD小鼠侧脑室，3-6周后，研究其认知功能改变，tau的磷酸化，Aβ的聚集以及其他相关的生化改变。
结果我们发现，STZ加重了3xTg-AD小鼠的短时记忆以及长时空间记忆障碍。我们还发现，STZ注射后，3xTg-AD小鼠的海马tau磷酸化水平进一步增高，脑内胰岛素通路异常，突触蛋白水平降低，以及β淀粉样蛋白水平改变。我们还通过定量PCR检测与AD相关的84个基因的表达情况，这些基因涉及APP的处理，tau/细胞骨架蛋白，突触功能，凋亡以，自噬，AD相关激酶，糖代谢，胰岛素通路以及mTOR通路。其中有20个基因的表达水平发生了变化。
结论这些结果提示了STZ可以损害3xTg-AD小鼠脑内的代谢以及其他细胞信号通路，证实了代谢损伤在AD疾病中的作用。
经鼻吸入胰岛素减轻了propofol麻醉3xTg-AD小鼠引起的tau高度磷酸化
目的探索经鼻吸入胰岛素对propofol导致的3xTg-AD小鼠tau高度磷酸化的影响。
方法我们通过给予3xTg-AD经鼻吸入（intranasal delivery, IND）胰岛素7天，于第七天IND结束后30分钟，给予propofol注射麻醉，麻醉后通过免疫蛋白印迹检测tau的磷酸化水平，相关激酶磷酸酶的激活，以及胰岛素信号通路的改变。
结果我们发现，propofol麻醉后30分钟，引起了tau在Thr181, Ser199, Thr205,Thr212, Thr231, Ser262/356, Ser396/404, Ser409位点的高度磷酸化，2小时候仍然存在。胰岛素IND增强了胰岛素信号通路各分子的表达与活性，降低了tau在Thr212, Ser262/356, Ser396/404, Ser409位点的磷酸化。同时胰岛素IND抑制了某些激酶的表达与激活，以及促进了PP2A的表达与激活。
结论我们的发现为术后认知功能障碍提供了可能的预防治疗途径
A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’sdisease: Similarities to and differences from the transgenic model(3xTg-AD mouse)
Background Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) andfamilial AD (FAD). Most AD cases are sporadic and result from multiple etiologicfactors, including environmental, genetic and metabolic factors, whereas FAD iscaused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP)genes. The most commonly used animal model for AD is the3xTg-AD transgenicmouse model, which harbors mutated presenilin1, APP and tau genes and thusrepresents a model of FAD. There is an unmet need to in the field to characterizeanimal models representing different AD mechanisms, so that potential drugs for SADcan be evaluated preclinically in these animal models.
Method A mouse model generated by intracerebroventricular (icv) administration ofstreptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study,we compared the non-cognitive and cognitive behaviors as well as biochemical andimmunohistochemical alterations between the icv-STZ mouse and the3xTg-ADmouse.
Results We found that both mouse models showed increased exploratory activity aswell as impaired learning and spatial memory. Both models also demonstratedneuroinflammation, altered synaptic proteins and insulin/IGF-1(insulin-like growthfactor-1) signaling, and increased hyperphosphorylated tau in the brain. The mostprominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the3xTg-AD mouse it was elevation of hyperphosphorylated tau.
Conclusion These observations demonstrate the behavioral and neuropathologicalsimilarities and differences between the icv-STZ mouse and the3xTg-AD mouse models and will help guide future studies using these two mouse models for thedevelopment of AD drugs.
Brain gene expression of a sporadic (icv-STZ mouse) and a familialmouse model (3xTg-AD mouse) of Alzheimer’s disease
Background Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) andfamilial AD (FAD). Most AD cases are sporadic and may result from multipleetiologic factors, including environmental, genetic and metabolic factors, whereasFAD is caused by mutations of presenilins or amyloid-β (Aβ) precursor protein (APP).The most commonly used mouse model for AD is3xTg-AD mouse, which isgenerated by over-expression of mutated presenilin1, APP and tau in the brain andthus represents a mouse model of FAD. A mouse model generated byintracerebroventricular (icv) administration of streptozocin (STZ), icv-STZ mouse,shows many aspects of SAD and has also been widely reported. Despite the wide useof these two models for AD research, differences in gene expression between them arenot known.
Method We report a comparison of expression profile of84AD-related genes in thehippocampus and the cerebral cortex between icv-STZ mice and3xTg-AD mice usinga custom-designed qPCR array. These genes are involved in APP processing,tau/cytoskeleton, synapse function, apoptosis and autophagy, AD-related proteinkinases, glucose metabolism, insulin signaling, and mTOR pathway.
Results We found altered expression of around20genes in both mouse models,which affected each of above categories. Many of these gene alterations wereconsistent with what was observed in AD brain previously. The expression of most ofthese altered genes was decreased or tended to be decreased in the hippocampus ofboth mouse models. Significant diversity in gene expression was found in the cerebralcortex between these two AD mouse models. More genes related to synaptic function were dysregulated in the3xTg-AD mice, whereas more genes related to insulinsignaling and glucose metabolism were down-regulated in the icv-STZ mice.
Conclusion Our observations demonstrate the similarities and differences betweenthe icv-STZ and the3xTg-AD mice, as well as provide detailed knowledge about thealterations of AD-related gene expression in these two mouse models. The presentstudy provides important fundamental knowledge of these two AD mouse models andwill help guide future studies using these two mouse models for the development ofAD drugs.
Intracerebroventricular administration of streptozotocin exacerbatescognitive deficits and brain abnormalities of3xTg-AD mice
Objective To investigate the role of metabolic insults in AD.
Method we injected streptozotocin (STZ), a diabetogenic compound if used in theperiphery, into the lateral ventricle of the6-month old3xTg-AD mice and studied thecognitive function, as well as tau phosphorylation, Aβ accumulation, and other relatedabnormalities in the mouse brains3-6weeks later.
Results We found that STZ exacerbated impairment of short-term and spatialreference memory in3xTg-AD mice. We also observed an increase of tauhyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling,and a decrease of synaptic plasticity and amyloid β peptides in the brain after STZtreatment. The expression of20AD-related genes, including those involved in theprocessing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulinsignaling, synaptic function, protein kinases and apoptosis, was altered, suggestingthat STZ disturbs multiple metabolic and cell signaling pathways in the brain.
Conclusion These findings demonstrate the role of metabolic insult in AD. Intranasal insulin prevents anesthesia induced hyperphosphorylationof tau in3xTg-AD miceObjective To investigate the effect of intranasal delivery of insulin onpropofol-induced hyperphosphorylation of tau in3xTg-AD mouse.Method3xTg-AD mice were given intranasal delivery of insulin or0.9%saline for7days.30minutes following the last doze, mice were subjected to intrapertonealinjection of propofol or the equivalent amount of vehicle. The phosphorylation of tau,activation of tau kinases and phosphatase, and activation of insulin signalingpathway were detected by western blots30minutes or2hours after propofoladministration.Results We found a significant increase in tau phosphorylation at Thr181, Ser199,Thr205, Thr212, Thr231, Ser262/356, Ser396/404, and Ser40930minutes followingpropofol injection in the frontal brain of the3xTg-AD mice. And thehyperphosphorylation at all these epitopes persisted for at least2hours. Intranasaldelivery of insulin ameliorated propofol induced hyperhosphorylation of tau atThr212, Ser262/356, Ser396/404, Ser409, which appeared to result from theinhibition of tau kinases and the activation of PP2A. We also confirmed theenhancement of insulin signaling pathway by intranasal delivery of insulin in thefrontal brain of the3xTg-AD mice.Conclusion Our findings provide a possible therapeutic way to treat anesthesiainduced post-operative cognitive decline.
背景阿尔茨海默病（Alzheimer’s Disease, AD）可以被分为散发性AD和家族性AD。绝大多数AD病例是散发性的，其发病原因非常多元化，包括环境因素，基因和代谢功能等，而家族性AD主要是由于早老素（presenilin，PS）或者是β淀粉样蛋白前体蛋白（amyloid-β precursor protein, APP）基因突变所致。目前，使用非常广泛的一个FAD动物模型是3xTg-AD转基因鼠。这种小鼠具有突变的人PS1， APP, tau基因。但是这个领域仍需要建立针对不同AD发病机制的的动物模型。只有这样，各种可能的治疗AD的药物才能在合适的动物模型上进行临床前期研究。
方法经侧脑室注射链脲霉素(streptozocin，STZ)，建立SAD小鼠模型(icv-STZ小鼠)。在本研究中，我们比较了icv-STZ小鼠与3xTg-AD小鼠在情感，认知行为学，生化以及免疫组化上的异同点。
结果我们发现，两种模型小鼠都存在探索行为活跃，学习及记忆障碍。两种模型小鼠脑内都存在着神经炎性反应，突触蛋白的改变，胰岛素通路的异常，以及高度磷酸化的tau。但是，在icv-STZ小鼠脑内，神经炎性反应更加明显，而在3xTg-AD小鼠脑内，高度磷酸化的tau尤为显著。
结论这些发现证实了icv-STZ小鼠与3xTg-AD小鼠在行为学和神经病理上的异同点。将为AD药物的研发在选择动物模型上提供指导。
散发性(icv-STZ小鼠)与家族性(3xTg-AD小鼠)阿尔茨海默病小鼠模型脑内AD相关基因的比较
研究背景阿尔茨海默病（Alzheimer’s Disease, AD）可以被分为散发性AD（Sporadic AD, SAD）以及家族性AD（Familial AD, FAD）。绝大多数的AD病例都是散发性的，其发病原因可能是多病因的，包括环境，基因和代谢因素。而FAD主要是由于早老素（Presenilin, PS）和β淀粉样前体蛋白(amyloid-β precursorprotein, APP)基因的突变所致。目前，使用非常广泛的一个FAD动物模型是3xTg-AD转基因鼠。这种小鼠具有突变的人PS1， APP, tau基因。而另外还有一种非转基因动物模型，即经侧脑室给予注射链脲霉素(streptozocin，STZ)，建立的模型(icv-STZ小鼠)具有SAD的很多特征，得到了越来越多的关注。尽管这两种模型目前都得到了广泛的关注和应用，其在基因表达上的异同点，仍未有研究。
方法我们通过定量PCR比较了icv-STZ小鼠与3xTg-AD小鼠在海马以及皮层的84个AD相关基因的表达情况。这些基因涉及APP的处理，tau/细胞骨架蛋白，突触功能，凋亡以，自噬，AD相关激酶，糖代谢，胰岛素通路以及mTOR通路。
结果我们发现，在以上所列的范围内，两种模型各有大约有20来个基因的表达发生了改变。很多基因的改变与已经被报道的在AD大脑内的改变一致。海马绝大多数有变化的基因为下调，这两种小鼠模型皮层的基因表达改变差异性更大，在3xTg-AD小鼠内，与突触相关的基因改变较多，而在icv-STZ小鼠内，与胰岛素通路以及糖代谢相关的基因下调更明显。
结论我们的研究证实了icv-STZ小鼠与3xTg-AD小鼠在AD相关基因表达上的异同点，并提供了非常详细的资料。此项研究也为将来基于此两种小鼠模型而进行的AD药物研究提供参考与指导。
经侧脑室注射链脲霉素进一步加重了3xTg-AD小鼠的认知功能障碍以及其他脑功能异常
目的研究代谢异常在AD疾病发生发展中的作用
方法我们将链脲霉素(streptozocin，STZ)（一种经腹腔注射可以诱导动物糖尿病的药物）注射到6个月龄的3xTg-AD小鼠侧脑室，3-6周后，研究其认知功能改变，tau的磷酸化，Aβ的聚集以及其他相关的生化改变。
结果我们发现，STZ加重了3xTg-AD小鼠的短时记忆以及长时空间记忆障碍。我们还发现，STZ注射后，3xTg-AD小鼠的海马tau磷酸化水平进一步增高，脑内胰岛素通路异常，突触蛋白水平降低，以及β淀粉样蛋白水平改变。我们还通过定量PCR检测与AD相关的84个基因的表达情况，这些基因涉及APP的处理，tau/细胞骨架蛋白，突触功能，凋亡以，自噬，AD相关激酶，糖代谢，胰岛素通路以及mTOR通路。其中有20个基因的表达水平发生了变化。
结论这些结果提示了STZ可以损害3xTg-AD小鼠脑内的代谢以及其他细胞信号通路，证实了代谢损伤在AD疾病中的作用。
经鼻吸入胰岛素减轻了propofol麻醉3xTg-AD小鼠引起的tau高度磷酸化
目的探索经鼻吸入胰岛素对propofol导致的3xTg-AD小鼠tau高度磷酸化的影响。
方法我们通过给予3xTg-AD经鼻吸入（intranasal delivery, IND）胰岛素7天，于第七天IND结束后30分钟，给予propofol注射麻醉，麻醉后通过免疫蛋白印迹检测tau的磷酸化水平，相关激酶磷酸酶的激活，以及胰岛素信号通路的改变。
结果我们发现，propofol麻醉后30分钟，引起了tau在Thr181, Ser199, Thr205,Thr212, Thr231, Ser262/356, Ser396/404, Ser409位点的高度磷酸化，2小时候仍然存在。胰岛素IND增强了胰岛素信号通路各分子的表达与活性，降低了tau在Thr212, Ser262/356, Ser396/404, Ser409位点的磷酸化。同时胰岛素IND抑制了某些激酶的表达与激活，以及促进了PP2A的表达与激活。
结论我们的发现为术后认知功能障碍提供了可能的预防治疗途径
A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’sdisease: Similarities to and differences from the transgenic model(3xTg-AD mouse)
Background Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) andfamilial AD (FAD). Most AD cases are sporadic and result from multiple etiologicfactors, including environmental, genetic and metabolic factors, whereas FAD iscaused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP)genes. The most commonly used animal model for AD is the3xTg-AD transgenicmouse model, which harbors mutated presenilin1, APP and tau genes and thusrepresents a model of FAD. There is an unmet need to in the field to characterizeanimal models representing different AD mechanisms, so that potential drugs for SADcan be evaluated preclinically in these animal models.
Method A mouse model generated by intracerebroventricular (icv) administration ofstreptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study,we compared the non-cognitive and cognitive behaviors as well as biochemical andimmunohistochemical alterations between the icv-STZ mouse and the3xTg-ADmouse.
Results We found that both mouse models showed increased exploratory activity aswell as impaired learning and spatial memory. Both models also demonstratedneuroinflammation, altered synaptic proteins and insulin/IGF-1(insulin-like growthfactor-1) signaling, and increased hyperphosphorylated tau in the brain. The mostprominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the3xTg-AD mouse it was elevation of hyperphosphorylated tau.
Conclusion These observations demonstrate the behavioral and neuropathologicalsimilarities and differences between the icv-STZ mouse and the3xTg-AD mouse models and will help guide future studies using these two mouse models for thedevelopment of AD drugs.
Brain gene expression of a sporadic (icv-STZ mouse) and a familialmouse model (3xTg-AD mouse) of Alzheimer’s disease
Background Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) andfamilial AD (FAD). Most AD cases are sporadic and may result from multipleetiologic factors, including environmental, genetic and metabolic factors, whereasFAD is caused by mutations of presenilins or amyloid-β (Aβ) precursor protein (APP).The most commonly used mouse model for AD is3xTg-AD mouse, which isgenerated by over-expression of mutated presenilin1, APP and tau in the brain andthus represents a mouse model of FAD. A mouse model generated byintracerebroventricular (icv) administration of streptozocin (STZ), icv-STZ mouse,shows many aspects of SAD and has also been widely reported. Despite the wide useof these two models for AD research, differences in gene expression between them arenot known.
Method We report a comparison of expression profile of84AD-related genes in thehippocampus and the cerebral cortex between icv-STZ mice and3xTg-AD mice usinga custom-designed qPCR array. These genes are involved in APP processing,tau/cytoskeleton, synapse function, apoptosis and autophagy, AD-related proteinkinases, glucose metabolism, insulin signaling, and mTOR pathway.
Results We found altered expression of around20genes in both mouse models,which affected each of above categories. Many of these gene alterations wereconsistent with what was observed in AD brain previously. The expression of most ofthese altered genes was decreased or tended to be decreased in the hippocampus ofboth mouse models. Significant diversity in gene expression was found in the cerebralcortex between these two AD mouse models. More genes related to synaptic function were dysregulated in the3xTg-AD mice, whereas more genes related to insulinsignaling and glucose metabolism were down-regulated in the icv-STZ mice.
Conclusion Our observations demonstrate the similarities and differences betweenthe icv-STZ and the3xTg-AD mice, as well as provide detailed knowledge about thealterations of AD-related gene expression in these two mouse models. The presentstudy provides important fundamental knowledge of these two AD mouse models andwill help guide future studies using these two mouse models for the development ofAD drugs.
Intracerebroventricular administration of streptozotocin exacerbatescognitive deficits and brain abnormalities of3xTg-AD mice
Objective To investigate the role of metabolic insults in AD.
Method we injected streptozotocin (STZ), a diabetogenic compound if used in theperiphery, into the lateral ventricle of the6-month old3xTg-AD mice and studied thecognitive function, as well as tau phosphorylation, Aβ accumulation, and other relatedabnormalities in the mouse brains3-6weeks later.
Results We found that STZ exacerbated impairment of short-term and spatialreference memory in3xTg-AD mice. We also observed an increase of tauhyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling,and a decrease of synaptic plasticity and amyloid β peptides in the brain after STZtreatment. The expression of20AD-related genes, including those involved in theprocessing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulinsignaling, synaptic function, protein kinases and apoptosis, was altered, suggestingthat STZ disturbs multiple metabolic and cell signaling pathways in the brain.
Conclusion These findings demonstrate the role of metabolic insult in AD. Intranasal insulin prevents anesthesia induced hyperphosphorylationof tau in3xTg-AD miceObjective To investigate the effect of intranasal delivery of insulin onpropofol-induced hyperphosphorylation of tau in3xTg-AD mouse.Method3xTg-AD mice were given intranasal delivery of insulin or0.9%saline for7days.30minutes following the last doze, mice were subjected to intrapertonealinjection of propofol or the equivalent amount of vehicle. The phosphorylation of tau,activation of tau kinases and phosphatase, and activation of insulin signalingpathway were detected by western blots30minutes or2hours after propofoladministration.Results We found a significant increase in tau phosphorylation at Thr181, Ser199,Thr205, Thr212, Thr231, Ser262/356, Ser396/404, and Ser40930minutes followingpropofol injection in the frontal brain of the3xTg-AD mice. And thehyperphosphorylation at all these epitopes persisted for at least2hours. Intranasaldelivery of insulin ameliorated propofol induced hyperhosphorylation of tau atThr212, Ser262/356, Ser396/404, Ser409, which appeared to result from theinhibition of tau kinases and the activation of PP2A. We also confirmed theenhancement of insulin signaling pathway by intranasal delivery of insulin in thefrontal brain of the3xTg-AD mice.Conclusion Our findings provide a possible therapeutic way to treat anesthesiainduced post-operative cognitive decline.
引文
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