Adipokines, Aging, and Alzheimers Disease

项目概要/摘要 高龄是阿尔茨海默病（AD）的主要危险因素。我们的计划是基于一个中心原则， 老年科学选择的途径和机制是老年和慢性疾病之间共享的， 一个人的知识可以告诉另一个人。mTORC1-S6K1激酶轴是肥胖激活的通路 在动物模型中，靶向这一途径可以延长寿命。这条路一直是 参与AD发病机制，临床前干预研究是有希望的。然而，药理学 抑制引起有害的副作用，阻碍了治疗应用。我们发现了一个Cdk5驱动的 mTORC1-S6K1通路的分叉导致衰老和肥胖。我们发现了一本小说，三重- S6K1的磷酸化形式（我们称之为S6K1 *）在C-末端的两个位点磷酸化，以及 Thr389，经典的mTORC 1激活位点。多位点磷酸化的S6K1指导新的 靶点，包括双功能tRNA合成酶、Glu-Pro tRNA合成酶（EPRS）、辅酶A合成酶 （CoASY）和脂质运载蛋白-2（Lcn2）。重要的是，携带EPRS磷酸缺陷突变的小鼠在关键的 Ser999残留量少，寿命延长约120天。Ser999 EPRS磷酸化是 关键长寿相关脂肪因子的脂肪细胞表达升高，包括单核细胞趋化蛋白- 1（MCP 1）和纤溶酶原激活物-1（PAI-1）。MCP 1是一种促炎蛋白，主要存在于 衰老相关分泌表型（SASP）; PAI-1是细胞衰老的标志物和介质， 衰老，以及编码PAI-1的基因SERPINE1中的无效突变，可防止生物衰老。 重要的是，这些新的、与年龄相关的S6K1 * 靶点也与AD进展有关。比如说， 血清MCP 1水平与小鼠AD模型和AD患者的认知功能下降相关，PAI-1 敲除或药理学抑制可减少小鼠中的AD。我们假设mTORC1-S6K1的延伸 通路及其效应物有助于AD的发作和进展，并且该通路的遗传抑制将 延缓AD发作并降低其严重程度，同时将不良副作用降至最低。此外，喂食高脂肪饮食的小鼠 表明肥胖通过共同途径影响衰老和AD进展。我们将测试这些假设， 两个具体目标。在第一个目标中，我们将阐明S6K1 * 通路在AD进展中的作用。AD- 易感小鼠将与我们开发的S6K1 * 通路抑制的两种遗传小鼠模型一起繁殖。 实验室，即EPRS磷酸缺陷敲入小鼠携带Ser999-丙氨酸突变，我们的新 开发了S6K1 Ser429-to-Ala小鼠模型，该模型缺乏扩展的S6K1 * 底物选择，但表现出 经典S6K1激酶活性不变。我们将确定S6K1 * 通路抑制对AD的影响， 病理学和不良认知副作用。在第二个目标中，我们将确定肥胖对 S6K1 * 通路介导的AD进展。我们的计划将建立新的机制和分子靶点 用于干预衰老过程和AD。

Project Summary/Abstract Advanced age is the leading risk factor for Alzheimer's disease (AD). Our program is based on a central tenet of geroscience that select pathways and mechanisms are shared between advanced age and chronic disease, and knowledge of one can inform the other. The mTORC1-S6K1 kinase axis is an obesity-activated pathway that restricts longevity, and targeting this pathway extends lifespan in animal models. This pathway has been implicated in AD pathogenesis, and pre-clinical intervention studies are promising. However, pharmacological inhibition causes harmful side-effects, deterring therapeutic application. We have discovered a Cdk5-driven bifurcation of the mTORC1-S6K1 pathway that contributes to aging and adiposity. We identified a novel, triply- phosphorylated form of S6K1 (we term S6K1*) phosphorylated at two sites in the C-terminus, as well as at Thr389, the classical mTORC1 activation site. Multi-site phosphorylated S6K1 directs phosphorylation of novel targets, including the dual function tRNA synthetase, Glu-Pro tRNA synthetase (EPRS), coenzyme A synthase (CoASY), and lipocalin-2 (Lcn2). Importantly, mice bearing a phospho-deficient mutation of EPRS at the critical Ser999 residue are lean and exhibit ~120-day lifespan extension. Ser999 EPRS phosphorylation is required for elevated adipocyte expression of key longevity-related adipokines, including monocyte chemoattractant protein- 1 (MCP1) and plasminogen-activator-1 (PAI-1). MCP1 is a pro-inflammatory protein predominant in the senescence-associated secretory phenotype (SASP); PAI-1 is a marker and mediator of cell senescence and aging, and a null mutation in SERPINE1, the gene encoding PAI-1, protects against biological aging. Importantly, these novel, age-related targets of S6K1* also are implicated in AD progression. For example, serum MCP1 level is associated with cognitive decline in mouse AD models and AD patients, and PAI-1 knockout, or pharmacologic inhibition, reduces AD in mice. We hypothesize that the extended mTORC1-S6K1 pathway and its effectors contribute to AD onset and progression, and that genetic inhibition of the pathway will retard AD onset and reduce its severity with minimal adverse side effects. Also, mice fed a high-fat diet will show that obesity influences aging and AD progression by a common pathway. We will test these hypotheses in two Specific Aims. In the first Aim, we will elucidate the role of the S6K1* pathway in AD progression. AD- susceptible mice will be bred with two genetic mouse models of S6K1* pathway inhibition developed in our laboratory, namely, EPRS phospho-deficient knock-in mice bearing a Ser999-to-Ala mutation, and our newly developed S6K1 Ser429-to-Ala mouse model, that lacks the extended S6K1* substrate selection, but exhibits unaltered canonical S6K1 kinase activity. We will determine effects of S6K1* pathway inhibition on AD pathology and adverse cognitive side-effects. In the second Aim we will determine the influence of obesity on S6K1* pathway-mediated AD progression. Our program will establish new mechanisms and molecular targets for intervention in the aging process and AD.