mTOR at the crossroad between aging and Alzheimer's disease

摘要 衰老是阿尔茨海默病（AD）及相关疾病的主要危险因素。但 衰老导致疾病发作的机制仍然难以捉摸。在这个应用程序中，我们将 试图确定可能将衰老与AD发病机制联系起来的关键信号通路。我们专注于 哺乳动物雷帕霉素靶蛋白（mTOR）是一种广泛表达的蛋白质，与衰老有着明确的联系。为 例如，小鼠中mTOR信号传导的减少延长了寿命并改善了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。大量的证据也表明mTOR是一种 在生理和病理条件下调节小胶质细胞功能的关键作用。比如说， 减少小胶质细胞中的mTOR信号传导减少促炎细胞因子，活性氧物质， 和其他有毒化合物。我们和其他人已经证明，mTOR信号是 在AD患者死后的大脑中增加。此外，我们表明，遗传和药理学的减少， mTOR在多种动物中改善淀粉样蛋白-β和tau病理，并改善突触功能和认知 模型AD。从机制上讲，我们鉴定了溶质载体家族8成员2（SLC 8A 2），一种神经元Na+/Ca 2 + 泵，作为mTOR和AD之间的可能联系。这些新颖而令人兴奋的发现使我们得出了以下结论 假设：mTOR代表衰老和AD之间的联系。具体目标1将确定小胶质细胞的作用， AD中的mTOR过度活跃。这些实验将有助于更好地了解mTOR如何调节 认知和神经退行性变。考虑到mTOR在衰老中的作用，这一目标是朝着 揭示了衰老和AD之间的联系具体目标2将阐明信号通路连接 mTOR与AD发病机制的关系。此外，如果成功的话，这一目标的结果将证实SLC 8A 2是一种新的 AD和相关疾病的分子靶点。具体目标3将确定mTOR在基因表达中的作用 在AD中观察到失调。本研究的结果将提供一个详细的mTOR基因调控网络， 衰老和AD的背景，并鉴定mTOR介导的基因表达特征， 老化和AD。影响：该应用程序将定义mTOR和AD之间的机制联系。此外，委员会认为， 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衰老的新机制。 AD的发展。阐明这些机制可能会发现几种新的推定的治疗 AD的目标。

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.