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（由申请人提供）：汇总数据表明，在阿尔茨海默病（AD）中，淀粉样蛋白-β（Aβ）和tau蛋白的积累导致记忆和其他认知功能的进行性恶化。然而，将Aβ和tau的积累与认知缺陷联系起来的分子途径仍然难以捉摸。在目前的资助周期中，我们已经表明，哺乳动物雷帕霉素靶蛋白（mTOR）在人类AD病例和AD动物模型的神经元和星形胶质细胞中过度活跃。我们发现，减少mTOR信号通过恢复蛋白质合成的缺陷和增加Aβ和tau蛋白的周转来改善小鼠中的AD样病理学。此外，我们的初步数据表明，过度活跃的mTOR信号传导通过促进坏死性凋亡（一种程序性坏死形式）而导致AD的神经退行性变。这一新颖而令人兴奋的发现可能回答了一个关键但尚未解决的问题：AD中细胞丢失的机制是什么。本申请的总体假设是过度活跃的mTOR通过破坏神经元和神经胶质中的蛋白质稳态导致细胞损失而促成AD发病机制。为此，我们提出三个具体目标。特异性目的1将检验以下假设：过度活跃的S6 K1（mTOR的下游效应子）通过改变蛋白质翻译而促成AD发病机制。我们的初步数据暗示S6 K1活动过度是AD中突触和认知缺陷的一种先前未被识别的机制。事实上，减少S6 K1活动过度改善了3xTg-AD小鼠中的AD样病理学。在这里，我们将使用互补的方法来剖析mTOR/S6 K1下游的机制，该机制将该途径与AD发病机制联系起来。具体目标2将检验以下假设：过度活跃的mTOR通过促进坏死性凋亡而促进AD中的神经变性。我们的初步数据表明，坏死性凋亡，程序性坏死的形式，有助于在AD的神经退行性变。与我们的假设一致，来自文献的数据表明mTOR在调节坏死性凋亡中起关键作用。为了验证我们的假设，我们将系统地调节具有不同mTOR活性水平的动物和细胞中的坏死性凋亡信号。具体目标3将检验星形胶质细胞中mTOR过度活跃导致Aβ蓄积、认知功能障碍和神经退行性变的假设。我们的初步数据显示，mTOR在AD小鼠和人类AD病例的星形胶质细胞中是过度活跃的。这是非常令人兴奋的，不仅因为mTOR调节星形胶质细胞的清道夫功能，而且因为已知活化的星形胶质细胞分泌可能诱导坏死性凋亡的毒性因子。我们将使用新开发的遗传工具来修饰AD动物模型和从人类AD病例中分离的人类初级星形胶质细胞中的mTOR。总之，本申请中提出的实验将确定mTOR、Aβ和tau积累以及神经变性和认知缺陷之间的机制联系。此外，鉴于mTOR信号在衰老中的作用，我们的研究结果可能揭示衰老促进AD发展的新机制。阐明这些机制将可能确定几个新的推定的治疗靶点。