Molecular interplay between Aβ, tau and mTOR: Mechanisms of neurodegeneration

Aβ、tau 和 mTOR 之间的分子相互作用：神经退行性变的机制

• 批准号: 9029256
• 负责人: Salvatore Oddo
• 金额: $ 113.42万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2020-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029256
• 关键词: Aging; Alzheimer' s Disease; Amyloid; Animal Model; Animals; Astrocytes; Brain; Cause of Death; Cell physiology; Cells; Cognition; Cognitive deficits; Data; Dementia; Deterioration; Development; Elderly; Elongation Factor; FRAP1 gene; Functional disorder; Genetic; Goals; Grant; Health; Homeostasis; Human; Hyperactive behavior; Impaired cognition; Lead; Learning; Link; Literature; Longevity; Mediating; Memory; Molecular; Mus; Necrosis; Nerve Degeneration; Neuroglia; Neurons; Pathogenesis; Pathology; Pathway interactions; Play; Protein Biosynthesis; Proteins; Proteomics; Research; Ribosomal Protein S6; Ribosomal Protein S6 Kinase; Role; Signal Pathway; Signal Transduction; Synapses; Testing; Tg2576; Translations; United States; abeta accumulation; base; cognitive function; improved; insight; mouse model; novel; programs; protein degradation; public health relevance; research study; tau Proteins; tau aggregation; therapeutic target; tool; uptake

 DESCRIPTION (provided by applicant): Converging data suggest that in Alzheimer's disease (AD), the accumulation of amyloid-β (Aβ) and tau leads to a progressive deterioration of memory and other cognitive functions. However, the molecular pathways linking the buildup of Aβ and tau to cognitive deficits remain elusive. During the current grant cycle, we have shown that the mammalian target of rapamycin (mTOR) is hyperactive in neurons and astrocytes of human AD cases and in animal models of AD. We found that reducing mTOR signaling improved AD-like pathology in mice by restoring deficits in protein synthesis and by increasing Aβ and tau turnover. Furthermore, our preliminary data suggest that hyperactive mTOR signaling contributes to neurodegeneration in AD by facilitating necroptosis, a programmed form of necrosis. This novel and exciting finding may answer a key, and yet unresolved question: which mechanisms govern cell loss in AD. The overall hypothesis of this application is that hyperactive mTOR contributes to AD pathogenesis by disrupting protein homeostasis in neurons and glia leading to cell loss. To this end, we propose three Specific Aims. Specific Aim 1 will test the hypothesis that hyperactive S6K1, a downstream effector of mTOR, contributes to AD pathogenesis by altering protein translation. Our preliminary data implicate S6K1 hyperactivity as a previously unidentified mechanism underlying synaptic and cognitive deficits in AD. Indeed, reducing S6K1 hyperactivity improves AD-like pathology in 3xTg-AD mice. Here we will use complementary approaches to dissect the mechanisms downstream of mTOR/S6K1 that link this pathway to AD pathogenesis. Specific Aim 2 will test the hypothesis that hyperactive mTOR contributes to neurodegeneration in AD by facilitating necroptosis. Our preliminary data indicate that necroptosis, a programmed form of necrosis, contributes to neurodegeneration in AD. Consistent with our hypothesis, data from the literature show that mTOR plays a key role in regulating necroptosis. To test our hypothesis, we will systematically modulate necroptotic signals in animals and cells with different levels of mTOR activity. Specific Aim 3 will test the hypothesis that hyperactive mTOR in astrocytes contributes to Aβ accumulation, cognitive dysfunction, and neurodegeneration. Our preliminary data show that mTOR is hyperactive in astrocytes of AD mice as well as of human AD cases. This is extremely exciting not only because mTOR regulates the scavenger functions of astrocytes but also because activated astrocytes are known to secrete toxic factors that may induce necroptosis. We will use newly developed genetic tools to modified mTOR in animal models of AD and in human primary astrocytes isolated from human AD cases. Taken together, the experiments proposed in this application will identify the mechanistic links among mTOR, Aβ and tau accumulation, as well as neurodegeneration and cognitive deficits. Furthermore, given the role of mTOR signaling in aging, our results may unveil new mechanisms by which aging contributes to the development of AD. Elucidating these mechanisms will likely identify several novel putative therapeutic targets.

 描述（由适用提供）：收敛数据表明，在阿尔茨海默氏病（AD）中，淀粉样蛋白-β（Aβ）的积累和tau的积累会导致记忆和其他认知功能的逐渐降低。但是，将Aβ和TAU堆积与认知定义的分子途径仍然难以捉摸。在当前的赠款周期中，我们已经表明，雷帕霉素的哺乳动物靶标（MTOR）在人类AD病例的神经元和星形胶质细胞和AD动物模型中具有多动。我们发现，通过恢复蛋白质合成中的定义并增加Aβ和TAU周转，减少MTOR信号传导改善了小鼠的AD样病理。此外，我们的初步数据表明，多动MTOR信号传导通过支持坏死性（一种已编程的坏死形式）来促进AD的神经变性。这个小说而令人兴奋的发现可能会回答一个钥匙，但尚未解决的问题：哪些机制控制了AD中的细胞损失。该应用的总体假设是，多动MTOR通过破坏神经元和神经胶质的蛋白质稳态而导致AD发病机理，导致细胞损失。为此，我们提出了三个具体目标。特定的目标1将检验以下假设：MTOR的下游效应子多动性S6K1通过改变蛋白质翻译而导致AD发病机理。我们的初步数据隐式S6K1多动症是AD中突触和认知定义的先前未知的机制。实际上，减少S6K1多动症可以改善3XTG-AD小鼠的AD样病理。在这里，我们将使用完整的方法来剖析MTOR/S6K1下游的机制，该机制将此途径与AD发病机理联系起来。特定的目标2将检验以下假设：多动MTOR通过促进坏死作用来促进AD的神经退行性。我们的初步数据表明，坏死性是一种编程的坏死形式，有助于AD中的神经变性。与我们的假设一致，文献的数据表明，mTOR在确定坏死作用中起关键作用。为了检验我们的假设，我们将系统地调节具有不同水平的MTOR活性的动物和细胞中的坏死信号。特定的目标3将检验星形胶质细胞中多动性mTOR的假设有助于Aβ的积累，认知功能障碍和神经变性。我们的初步数据表明，MTOR在AD小鼠和人类AD病例的星形胶质细胞中具有多动。这不仅是因为MTOR调节了星形胶质细胞的清道夫功能，而且还因为活化的星形胶质细胞是可能诱导坏死的秘密有毒因素，这是非常令人兴奋的。我们将使用新开发的遗传工具在AD的动物模型和从人类AD病例中分离的人类主要星形胶质细胞中修改MTOR。综上所述，本应用程序中提出的实验将确定MTOR，Aβ和TAU积累之间的机械联系，以及神经变性和认知缺陷。此外，鉴于MTOR信号在衰老中的作用，我们的结果可能会揭示衰老有助于AD发展的新机制。阐明这些机制可能会确定几个新型的推定治疗靶标。