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。尽管如此， 衰老导致疾病发生的机制仍然难以捉摸。在此应用程序中，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。我们将重点放在 哺乳动物雷帕霉素的靶标(MTOR)，一种普遍表达的蛋白质，与衰老有既定的联系。为 例如，小鼠mTOR信号的减少延长了寿命，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。大量证据也表明mTOR正在发挥作用。 在生理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信号会减少促炎细胞因子、活性氧的分泌， 以及来自激活的小胶质细胞的其他有毒化合物。我们和其他人已经证明了mTOR信号是 死后人类阿尔茨海默病大脑中的含量增加。此外，我们还表明，遗传和药物方面的减少 MTOR改善多种动物的淀粉样蛋白-β和tau病理，改善突触功能和认知能力 广告模特。从机制上讲，我们鉴定了溶质载体家族8成员2(SLC8A2)，一个神经细胞的Na+/Ca2+ Pump，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。特定目标1将确定小胶质细胞的作用 阿尔茨海默病的多动症。这些实验将有助于更好地理解mTOR是如何调节的 阿尔茨海默病的认知和神经退行性改变。鉴于mTOR在衰老中的作用，这一目标是迈向 揭示衰老和阿尔茨海默病的联系机制。具体目标2将阐明信号通路之间的联系 MTOR与AD发病机制有关。此外，如果成功，这一目标的结果将证实SLC8A2是一种新颖的 AD及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 在阿尔茨海默病中观察到调节失调。这一目标的结果将提供一个详细的mTOR基因调控网络 衰老和阿尔茨海默病的关系，并确定mTOR介导的基因表达特征在 衰老和AD。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，我们的结果可能揭示衰老的新机制 对AD的发展做出了贡献。阐明这些机制可能会确定几种新的假定的治疗方法 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.