Adipokines, Aging, and Alzheimers Disease

项目摘要/摘要 高龄是阿尔茨海默病(AD)的主要危险因素。我们的计划基于一个中心原则，即 选择途径和机制的老年学在高龄和慢性病之间是共享的， 而对其中一个的了解可以告知另一个。MTORC1-S6K1激动轴是肥胖激活的途径 这限制了寿命，而靶向这一途径延长了动物模型的寿命。这条路一直是 阿尔茨海默病的发病机制和临床前干预研究前景看好。然而，药理学 抑制会导致有害的副作用，阻碍治疗应用。我们发现了一种由CDK5驱动的 导致衰老和肥胖的mTORC1-S6K1通路的分叉。我们发现了一部小说，三重- S6K1的磷酸化形式(我们称为S6K1*)在C末端的两个位点以及在 Thr389，经典的mTORC1激活位点。多位点磷酸化的S6K1直接磷酸化新基因 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Lipocalin-2(Lcn2)。重要的是，携带Eprs缺磷突变的小鼠在危急时刻 Ser999残留物很瘦，寿命延长了约120天。Ser999 EPRS磷酸化是必需的 脂肪细胞表达与长寿相关的关键脂肪因子，包括单核细胞趋化蛋白- 1(MCP1)和纤溶酶原激活物-1(PAI-1)。MCP1是一种促炎蛋白，主要存在于 衰老相关分泌表型(SASP)；PAI-1是细胞衰老的标志和介体 衰老，以及编码PAI-1的基因SERPINE1的零突变，可以防止生物衰老。 重要的是，S6K1*的这些新的、与年龄相关的靶点也与AD的进展有关。例如, 血清MCP1水平与小鼠AD模型和AD患者认知功能减退及PAI-1相关 基因敲除或药物抑制可以减少小鼠的阿尔茨海默病。我们假设扩展的mTORC1-S6K1 该通路及其效应器参与了AD的发生和发展，而该通路的遗传抑制将 延缓阿尔茨海默病的发病，减轻其严重程度，副作用最小。此外，喂食高脂肪食物的小鼠将 表明肥胖通过一条共同的途径影响衰老和AD进展。我们将在以下方面测试这些假设 有两个明确的目标。在第一个目标中，我们将阐明S6K1*通路在AD进展中的作用。广告- 用本实验室建立的两种S6K1*通路抑制基因小鼠模型培育易感小鼠 实验室，即携带Ser999到Ala突变的EPRS磷酸缺陷型敲入小鼠，以及我们新的 开发了S6K1 Ser429-to-ALA小鼠模型，缺少扩展的S6K1*底物选择，但表现出 标准的S6K1激酶活性没有改变。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.