mTOR at the crossroad between aging and Alzheimer's disease

mTOR 处于衰老和阿尔茨海默氏病的十字路口

• 批准号: 9764038
• 负责人: Salvatore Oddo
• 金额: $ 14.64万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2020-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764038
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Autopsy; Brain Diseases; Calcium; Cause of Death; Cognition; Cognitive; Cognitive deficits; Data; Dementia; Development; Disease; Elderly; Encephalitis; Etiology; Event; FRAP1 gene; Family; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Human; Hyperactive behavior; In Vitro; Inflammatory; Insulin; Knock-in Mouse; Laboratories; Link; Longevity; Mediating; Microglia; Modeling; Molecular; Molecular Target; Mus; Nerve Degeneration; Neurons; Obesity; Onset of illness; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pharmacology; Phosphotransferases; Physiological; Play; Poison; Positioning Attribute; Proteins; Pump; Reactive Oxygen Species; Regulator Genes; Role; Signal Pathway; Signal Transduction; Synapses; Tauopathies; Testing; Toxic effect; Translations; United States; Viral Vector; age related; aging brain; autosomal dominant mutation; causal variant; clinically translatable; cognitive function; cohort; cytokine; experimental study; healthspan; immune system function; improved; insulin sensitivity; member; motor disorder; mouse model; novel; screening; solute; synaptic function; tau Proteins; therapeutic target; transcriptomics

Abstract Aging is the primary risk factor for Alzheimer's disease (AD) and related disorders. Nevertheless, the mechanisms by which aging contributes to the onset of the disease remain elusive. In this application, we will attempt to identify critical signaling pathways that might link aging to AD pathogenesis. We focus on the mammalian target of rapamycin (mTOR), a ubiquitously expressed protein with an established link to aging. For example, reduction of mTOR signaling in mice extends lifespan and improves age-dependent motor dysfunction, insulin sensitivity, obesity, and immune system function. A large body of evidence also points to mTOR as playing a pivotal role in regulating microglia function during physiological and pathological conditions. For instance, reducing mTOR signaling in microglia reduces secretion of pro-inflammatory cytokines, reactive oxygen species, and other toxic compounds from activated microglia. We and others have shown that mTOR signaling is increased in postmortem human AD brains. In addition, we show that genetic and pharmacological reduction of mTOR ameliorates amyloid-β and tau pathology, and improves synaptic function and cognition in multiple animal models AD. Mechanistically, we identified the Solute Carrier Family 8 Member 2 (SLC8A2), a neuronal Na+/Ca2+ pump, as a possible link between mTOR and AD. These novel and exciting findings led us to the following hypothesis: mTOR represents a link between aging and AD. Specific Aim 1 will identify the role of microglial mTOR hyperactivity in AD. These experiments will lead to a better understanding of how mTOR modulates cognition and neurodegeneration in AD. Given the role of mTOR in aging, this aim is a critical step toward unveiling the mechanisms linking aging and AD. Specific Aim 2 will elucidate the signaling pathways linking mTOR to AD pathogenesis. In addition, if successful, the results of this aim will corroborate SLC8A2 as a novel molecular target for AD and related disorders. Specific Aim 3 will identify the role of mTOR in the gene expression dysregulation observed in AD. The results of this Aim will provide a detailed mTOR gene regulatory network in the context of aging and AD and identify an mTOR-mediated gene expression signature that is unique between aging and AD. Impact: This application will define the mechanistic links between mTOR and AD. 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 for AD.

抽象的 衰老是阿尔茨海默氏病（AD）和相关疾病的主要危险因素。然而， 衰老导致疾病发作的机制仍然难以捉摸。在此应用程序中，我们将 尝试识别可能将衰老与AD发病机理联系起来的关键信号通路。我们专注于 雷帕霉素（MTOR）的哺乳动物靶标，一种无处不在的蛋白质，与衰老有建立联系。 例如，小鼠MTOR信号的降低可扩展寿命并改善年龄依赖性运动功能障碍， 胰岛素敏感性，肥胖和免疫系统功能。大量证据也表明MTOR是玩 在身体和病理条件下调节小胶质细胞功能的关键作用。例如， 减少小胶质细胞中的MTOR信号传导减少了促炎性细胞因子，活性氧的分泌， 以及活化小胶质细胞的其他有毒化合物。我们和其他人已经表明mTOR信号是 死后人类广告大脑的增加。此外，我们表明了遗传和药物的减少 MTOR改善淀粉样β和TAU病理学，并改善多种动物的突触功能和认知 型号AD。从机械上讲，我们确定了溶质载体家族8成员2（SLC8A2），神经元Na+/Ca2+ 泵，作为MTOR和AD之间的可能链接。这些小说而令人兴奋的发现使我们陷入了以下 假设：MTOR代表衰老与AD之间的联系。特定的目标1将确定小胶质细胞的作用 AD中的MTOR多动症。这些实验将使MTOR如何调节更好地理解 AD中的认知和神经变性。鉴于MTOR在衰老中的作用，此目标是迈向的关键一步 揭示关联衰老和AD的机制。特定的目标2将阐明链接的信号通路 MTOR到AD发病机理。此外，如果成功的话，这个目标的结果将证实SLC8A2作为一种新颖 AD和相关疾病的分子靶标。特定的目标3将确定MTOR在基因表达中的作用 在AD中观察到的失调。此目标的结果将提供详细的MTOR基因调节网络 衰老和AD的上下文，并识别MTOR介导的基因表达特征，这是独特的 衰老和广告。影响：此应用程序将定义MTOR和AD之间的机械联系。此外， 鉴于MTOR信号在衰老中的作用，我们的结果可能会揭示出衰老贡献的新机制 发展广告。阐明这些机制可能会识别几种新型的推定治疗性 AD的目标。