Adipokines, Aging, and Alzheimers Disease

脂肪因子、衰老和阿尔茨海默病

• 批准号: 10601044
• 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/10601044
• 关键词: 3xTg-AD mouse; Acceleration; 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; Behavior; Biological Aging; Biological Markers; Brain; Breeding; CCL2 gene; Cell Aging; Chronic; Chronic Disease; Clinical Trials; Coenzyme A; Cognitive; Cognitive deficits; Communities; Complex; Cyclin-Dependent Kinases; Data; Development; Disease Progression; Disease susceptibility; Elderly; Exhibits; Genes; Genetic; Genetic Code; Genetic Diseases; Geroscience; High Fat Diet; Impaired cognition; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intervention; Intervention Studies; Knock-in; Knock-in Mouse; Knock-out; Knowledge; LCN2 gene; Laboratories; Learning; Ligase; Longevity; Mediating; Mediator; Memory; Metabolic Pathway; Molecular; Molecular Target; Mus; Mutant Strains Mice; Mutation; Obesity; Onset of illness; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Plasminogen Activator; Process; Proteins; Role; SERPINE1 gene; Serum; Severities; Signal Transduction; Site; Testing; Therapeutic; Thinness; Tissue Donors; Tissue Transplantation; Transfer RNA; Transplantation; Visceral; Wild Type Mouse; adipokines; age related; cognitive function; diet-induced obesity; inhibitor; member; mouse model; neuropathology; novel; novel therapeutics; null mutation; pharmacologic; pre-clinical; programs; proline-tRNA; senescence; side effect; 3xTg-AD mouse; Acceleration; 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; Behavior; Biological Aging; Biological Markers; Brain; Breeding; CCL2 gene; Cell Aging; Chronic; Chronic Disease; Clinical Trials; Coenzyme A; Cognitive; Cognitive deficits; Communities; Complex; Cyclin-Dependent Kinases; Data; Development; Disease Progression; Disease susceptibility; Elderly; Exhibits; Genes; Genetic; Genetic Code; Genetic Diseases; Geroscience; High Fat Diet; Impaired cognition; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intervention; Intervention Studies; Knock-in; Knock-in Mouse; Knock-out; Knowledge; LCN2 gene; Laboratories; Learning; Ligase; Longevity; Mediating; Mediator; Memory; Metabolic Pathway; Molecular; Molecular Target; Mus; Mutant Strains Mice; Mutation; Obesity; Onset of illness; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Plasminogen Activator; Process; Proteins; Role; SERPINE1 gene; Serum; Severities; Signal Transduction; Site; Testing; Therapeutic; Thinness; Tissue Donors; Tissue Transplantation; Transfer RNA; Transplantation; Visceral; Wild Type Mouse; adipokines; age related; cognitive function; diet-induced obesity; inhibitor; member; mouse model; neuropathology; novel; novel therapeutics; null mutation; pharmacologic; pre-clinical; programs; proline-tRNA; 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.

项目摘要/摘要 高龄是阿尔茨海默氏病（AD）的主要危险因素。我们的计划基于 在高龄和慢性疾病之间共享选择途径和机制的Geroscience， 一个人的知识可以告知另一个。 MTORC1-S6K1激酶轴是肥胖激活的途径 这限制了寿命，并且针对该途径会延长动物模型中的寿命。这条路已经 与AD发病机理和临床前干预研究有关。但是，药理学 抑制作用会导致有害的副作用，阻止治疗应用。我们发现了CDK5驱动的 MTORC1-S6K1途径的分叉，导致衰老和肥胖。我们确定了一本小说三项 - S6K1的磷酸化形式（我们称为S6K1*）在C末端的两个位点磷酸化，以及AT THR389，经典的MTORC1激活位点。多站点磷酸化的S6K1指导新型的磷酸化 靶标，包括双重函数tRNA合成酶，GLU-PRO tRNA合成酶（EPRS），辅酶A合酶 （Coasy）和lipocalin-2（LCN2）。重要的是，在临界处具有EPR的磷酸化缺陷突变的小鼠 Ser999残留物为瘦，展示〜120天的寿命延长。 SER999 EPRS磷酸化是需要的 关键寿命相关脂肪因子的脂肪细胞表达升高，包括单核细胞趋化剂蛋白 1（MCP1）和纤溶酶原活化剂1（PAI-1）。 MCP1是一种促炎蛋白 衰老相关的分泌表型（SASP）； PAI-1是细胞衰老的标记和中介者 衰老和编码PAI-1的基因中的衰老和无效突变可防止生物衰老。 重要的是，这些新型S6K1*的新型年龄相关靶标也与AD进展有关。例如， 血清MCP1水平与小鼠AD模型和AD患者的认知下降有关，PAI-1 敲除或药理学抑制可减少小鼠的AD。我们假设扩展的MTORC1-S6K1 途径及其效应子有助于AD的发作和进展，途径的遗传抑制作用将 延迟AD发作并通过最小的不良副作用来降低其严重程度。此外，喂养高脂饮食的小鼠将 表明肥胖会通过通用途径影响衰老和AD的进展。我们将在 两个具体的目标。在第一个目标中，我们将阐明S6K1*途径在AD进程中的作用。广告- 易感小鼠将用S6K1的两个遗传小鼠模型*在我们的 实验室，即具有Ser999-To-Ala突变的EPRS缺陷型敲入小鼠，而我们的新近 开发的S6K1 Ser429至Ala鼠标模型，缺乏扩展的S6K1*基板选择，但展示 未改变的规范S6K1激酶活性。我们将确定S6K1*途径抑制对AD的影响 病理和不良认知副作用。在第二个目标中，我们将确定肥胖对 S6K1*途径介导的AD进展。我们的计划将建立新的机制和分子目标 用于干预衰老过程和广告。