Adipokines, Aging, and Alzheimers Disease

脂肪因子、衰老和阿尔茨海默病

• 批准号: 10378046
• 负责人: PAUL L FOX
• 金额: $ 47.45万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378046
• 关键词: 3xTg-AD mouse; Adipocytes; Adipose tissue; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amino Acyl-tRNA Synthetases; Amish; Animal Model; Animals; Behavior; Biological Aging; Biological Markers; Brain; CCL2 gene; Cell Aging; Chronic; Chronic Disease; Clinical Trials; Coenzyme A; Cognitive; Cognitive deficits; Complex; Cyclin-Dependent Kinases; Data; Development; Disease Progression; Elderly; Exhibits; Fatty acid glycerol esters; Genetic; Genetic Code; Genetic Diseases; Geroscience; High Fat Diet; Impaired cognition; Inflammation; Inflammatory; Insulin; Intervention; Intervention Studies; Knock-in; Knock-in Mouse; Knock-out; Knowledge; LCN2 gene; Laboratories; Lead; Learning; Longevity; Mediating; Mediator of activation protein; Memory; Metabolic Pathway; Molecular; Molecular Target; Mus; Mutant Strains Mice; Mutation; Obesity; Onset of illness; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Plasminogen Activator; Process; Proteins; Role; SERPINE1 gene; Serum; Severities; Signal Transduction; Site; Testing; Therapeutic; Thinness; Tissue Donors; Transfer RNA; Transplantation; Visceral; Wild Type Mouse; adipokines; age related; base; cognitive function; diet-induced obesity; inhibitor; member; mouse model; neuropathology; novel; null mutation; pre-clinical; programs; prolylglutamic acid; senescence; side effect

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.

项目概要/摘要 高龄是阿尔茨海默病 (AD) 的主要危险因素。我们的计划基于以下核心原则： 老年科学选择高龄和慢性疾病之间共享的途径和机制， 一个人的知识可以告知另一个人。 mTORC1-S6K1 激酶轴是肥胖激活的途径 限制寿命，而针对该途径可以延长动物模型的寿命。这条路已经 与 AD 发病机制有关，临床前干预研究前景广阔。然而，药理 抑制会导致有害的副作用，阻碍治疗应用。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。我们确定了一部小说，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 Thr389，经典的 mTORC1 激活位点。多位点磷酸化 S6K1 直接磷酸化新型 靶标，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，在关键时刻携带 EPRS 磷酸缺陷突变的小鼠 Ser999 残留物很精简，并且寿命延长约 120 天。 Ser999 EPRS 磷酸化是必需的 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 (MCP1) 和纤溶酶原激活剂-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是细胞衰老的标志物和介质 衰老，编码 PAI-1 的基因 SERPINE1 的无效突变可以防止生物衰老。 重要的是，这些新的、与年龄相关的 S6K1* 靶点也与 AD 进展有关。例如， 血清 MCP1 水平与小鼠 AD 模型和 AD 患者的认知能力下降有关，而 PAI-1 基因敲除或药物抑制可减少小鼠的 AD。我们假设扩展的 mTORC1-S6K1 通路及其效应子有助于 AD 的发病和进展，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，喂食高脂肪饮食的老鼠会 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。广告- 易感小鼠将与我们开发的两种 S6K1* 通路抑制基因小鼠模型一起培育。 实验室，即带有 Ser999-to-Ala 突变的 EPRS 磷酸缺陷敲入小鼠，以及我们的新 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 激酶活性未改变。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目标 干预衰老过程和 AD。