{"title":"实验性散发性阿尔茨海默病中失调的 mTOR 网络。","authors":"Suzanne M de la Monte, Ming Tong","doi":"10.3389/fncel.2024.1432359","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD.</p><p><strong>Objective: </strong>This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration.</p><p><strong>Methods: </strong>Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules.</p><p><strong>Results: </strong>Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL <sup>pY1135/1136</sup>-IGF-1R, Akt, PTEN, <sup>pS380</sup>-PTEN, <sup>pS2448</sup>-mTOR, p70S6K, <sup>pT412</sup>-p70S6K, p/T-<sup>pT412</sup>-p70S6K, p/T-Rictor, and p/T-Raptor.</p><p><strong>Conclusion: </strong>Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461251/pdf/","citationCount":"0","resultStr":"{\"title\":\"Dysregulated mTOR networks in experimental sporadic Alzheimer's disease.\",\"authors\":\"Suzanne M de la Monte, Ming Tong\",\"doi\":\"10.3389/fncel.2024.1432359\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD.</p><p><strong>Objective: </strong>This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration.</p><p><strong>Methods: </strong>Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules.</p><p><strong>Results: </strong>Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL <sup>pY1135/1136</sup>-IGF-1R, Akt, PTEN, <sup>pS380</sup>-PTEN, <sup>pS2448</sup>-mTOR, p70S6K, <sup>pT412</sup>-p70S6K, p/T-<sup>pT412</sup>-p70S6K, p/T-Rictor, and p/T-Raptor.</p><p><strong>Conclusion: </strong>Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.</p>\",\"PeriodicalId\":12432,\"journal\":{\"name\":\"Frontiers in Cellular Neuroscience\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-09-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461251/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in Cellular Neuroscience\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3389/fncel.2024.1432359\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Cellular Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fncel.2024.1432359","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
背景:除了标志性的淀粉样蛋白-β斑块和神经纤维缠结外,阿尔茨海默病(AD)还表现出通过胰岛素和胰岛素样生长因子(IGF)网络与雷帕霉素机制靶点(mTOR)串联的代谢信号失调。它对大脑结构和功能的广泛影响表明,mTOR很可能是AD的一个重要治疗靶点:本研究描述了散发性 AD 神经变性大鼠模型中颞叶(TL)mTOR 信号传导异常的特征:方法:给长埃文斯大鼠脑室内注射链脲佐菌素(ic-STZ)或生理盐水(对照组),4周后对其进行神经行为测试,最后采集颞叶进行组织病理学研究,并测量AD生物标记物、神经炎症/氧化应激标记物以及胰岛素/IGF-1-Akt-mTOR通路信号分子的总量和磷酸化量:结果:接受ic-STZ治疗的大鼠在旋转木马(RR)和莫里斯水迷宫(MWM)测试中表现出明显的能力受损、脑萎缩、TL和海马神经元及白质变性,TL pTau、AβPP、Aβ、AChE、4-HNE和GAPDH升高,泛素、IL-2、IL-6和IFN-γ免疫活性降低。此外,ic-STZ还降低了TL pY1135/1136-IGF-1R、Akt、PTEN、pS380-PTEN、pS2448-mTOR、p70S6K、pT412-p70S6K、p/T-pT412-p70S6K、p/T-Rictor和p/T-Raptor:实验性ic-STZ诱导的散发性AD型神经退行性变和神经行为功能障碍与抑制与能量代谢、可塑性和白质完整性相关的mTOR信号网络有关。
Dysregulated mTOR networks in experimental sporadic Alzheimer's disease.
Background: Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD.
Objective: This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration.
Methods: Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules.
Results: Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL pY1135/1136-IGF-1R, Akt, PTEN, pS380-PTEN, pS2448-mTOR, p70S6K, pT412-p70S6K, p/T-pT412-p70S6K, p/T-Rictor, and p/T-Raptor.
Conclusion: Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.
期刊介绍:
Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.