Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration.

晚期糖基化终产物 (AGE) 作为介导神经退行性变的代谢副产物。

• 批准号: 10624982
• 负责人: Pankaj Kapahi
• 金额: $ 64.69万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10624982
• 关键词: Acceleration; Adult; Advanced Glycosylation End Products; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Arginine; Binding Proteins; Biochemical; Biochemical Pathway; Caenorhabditis elegans; Cellular Stress; Cerebrospinal Fluid; Chronic; Complement; Complex; DNA; Data; Defect; Diabetes Mellitus; Diet; Disease; Drug Metabolic Detoxication; Exhibits; Fatty Acids; Genes; Genetic; Glucose; Glutathione; Glycolysis; Goals; Human; Hyperglycemia; Hypersensitivity; Inflammation; Ketone Bodies; Lactoylglutathione Lyase; Link; Lipids; Longevity; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Obesity; Paralysed; Pathogenesis; Pathology; Pathway interactions; Post-Translational Protein Processing; Production; Proteins; Pseudouridine; Pyruvaldehyde; RNA Splicing; Reaction; Risk; Role; Series; Serum; Testing; Touch sensation; Toxic effect; Work; age effect; age related; age related neurodegeneration; anaerobic glycolysis; base; cell injury; chemical synthesis; cofactor; crosslink; diabetic; fatty acid oxidation; feeding; glucose metabolism; lipid metabolism; mortality; mutant; neurotoxicity; new therapeutic target; normal aging; overexpression; pharmacologic; protein aggregation; proteotoxicity; response; tau Proteins; tau mutation; therapeutic target

PROJECT SUMMARY/ ABSTRACT Aging and chronic hyperglycemia results in several metabolic and biochemical perturbations including elevation of a series of highly reactive α-dicarbonyl compounds (α-DCs, e.g., Methylglyoxal(MGO). α-DCs are unavoidable byproducts largely of anaerobic glycolysis which react indiscriminately with proteins, lipids, and DNA to yield a heterogeneous group of molecules called advanced glycation end products (AGEs). A large body of evidence has linked accelerated glucose metabolism and diabetes to neurodegenerative diseases like Alzheimer's disease (AD). We hypothesize that toxic byproducts of glucose metabolism that result in the formation of AGEs explain the enhanced risk of AD due to hyperglycemia and diabetes. In support of this AGEs in serum and AGE crosslinking in protein aggregates have been associated with enhanced neurodegeneration in AD. However, AGEs are hard to model as they take years to accumulate in humans and the mechanism by which they cause cellular damage remains to be elucidated. To overcome this gap, we have established C. elegans (worm) models that significantly accumulate α-DCs and AGEs, exhibiting several age- related pathologies, such as hypersensitivity to touch, neuronal damage, paralysis, and early mortality, all within three weeks of adulthood. In addition, we have observed that direct administration of synthetic methylglyoxal derived AGEs can directly cause neurotoxicity. Furthermore, we have observed that a C. elegans model overexpressing the pro-aggregating form of tau, that has been implicated in Alzheimer's disease, is sensitive to feeding either glucose or AGEs in the diet. In this proposal, we will test the hypothesis that changes in glucose and lipid metabolism pathways, especially with age, influence MGO and associated AGEs thereby causing neurodegeneration associated with AD. We will also determine the mechanisms by which AGEs influence metabolic dysfunction and contribute to neurodegeneration in AD. In Aim 1 we will explore a causal role for the effects of AGEs on neurodegeneration in normal aging and in Alzheimer's disease models using synthetically derived AGEs. We will also examine the role of age-associated changes in glucose metabolism in influencing the levels of MGO and AGEs and enhancing neurodegeneration in models of AD. In Aim 2 we will determine the relationship between lipid metabolism and production of AGEs. We will genetically and pharmacologically manipulate fatty acid oxidation pathways to examine their influence on modulating neurodegeneration in normal aging and AD models through modulation of AGEs. In Aim 3 we propose to identify the mechanisms by which AGEs mediate their toxicity leading to inhibition of fatty acid oxidation and neurodegeneration. We will identify AGE-binding proteins and therapeutic targets to modulate AGE-related neurodegeneration. These studies will identify several genetic and pharmacological targets to ameliorate AGEs and slow down the progression of neurodegeneration in AD.

项目概要/摘要 衰老和慢性高血糖会导致多种代谢和生化紊乱，包括 一系列高活性α-二羰基化合物（α-DC，例如甲基乙二醛（MGO））的升高。α-DC 主要是无氧糖酵解不可避免的副产物，它们与蛋白质、脂质、 和 DNA 产生一组异质分子，称为晚期糖基化终产物 (AGE)。 大量证据表明葡萄糖代谢加速和糖尿病与神经退行性疾病有关 我们服用了葡萄糖代谢的有毒副产品，例如阿尔茨海默病（AD）。 AGEs 的形成解释了高血糖和糖尿病导致 AD 风险增加。 血清中的 AGE 和蛋白质聚集体中的 AGE 交联与增强 然而，AGEs 很难建模，因为它们需要数年时间才能在人类体内积累。 它们引起细胞损伤的机制仍有待阐明。为了克服这一差距，我们已经做到了。 建立了线虫（蠕虫）模型，该模型显着积累 α-DC 和 AGE，表现出多种年龄- 相关病理，例如触摸过敏、神经元损伤、瘫痪和早期死亡，所有 此外，我们还观察到在成年后三周内直接施用合成药物。 甲基乙二醛衍生的 AGE 可以直接引起神经毒性。此外，我们观察到 C. 线虫模型过度表达 tau 蛋白的促聚集形式，这与阿尔茨海默病有关 疾病对饮食中添加葡萄糖或 AGE 很敏感。在本提案中，我们将检验这一假设。 葡萄糖和脂质代谢途径的变化，尤其是随着年龄的增长，会影响 MGO 和相关的 AGEs 从而导致与 AD 相关的神经变性，我们还将通过以下方式确定其机制。 AGE 会影响代谢功能障碍并导致 AD 中的神经变性。 在目标 1 中，我们将探讨 AGEs 对正常衰老和神经退行性变的影响的因果作用。 使用合成 AGE 建立阿尔茨海默病模型 我们还将研究与年龄相关的作用。 葡萄糖代谢的变化影响 MGO 和 AGE 的水平并加剧神经退行性变 在 AD 模型中，我们将确定脂质代谢与 AGE 产生之间的关系。 我们将从遗传和药理学角度操纵脂肪酸氧化途径来检查其影响 在目标 3 中，我们通过调节 AGE 来调节正常衰老和 AD 模型中的神经退行性变。 提议确定 AGE 介导其毒性从而抑制脂肪酸的机制 我们将确定 AGE 结合蛋白和调节的治疗靶点。 这些研究将确定一些与 AGE 相关的神经退行性疾病的遗传和药理学靶标。 改善 AGE 并减缓 AD 神经变性的进展。

项目成果

Trimethylamine modulates dauer formation, neurodegeneration, and lifespan through tyra-3/daf-11 signaling in Caenorhabditis elegans.

三甲胺通过秀丽隐杆线虫中的 tyra-3/daf-11 信号传导调节 dauer 形成、神经变性和寿命。

• 发表时间: 2021
• 影响因子: 7.8
• 作者: Khanna, Amit;Sellegounder, Durai;Kumar, Jitendra;Chamoli, Manish;Vargas, Miguel;Chinta, Shankar J;Rane, Anand;Nelson, Christopher;Peiris, T Harshani;Brem, Rachel;Andersen, Julie;Lithgow, Gordon;Kapahi, Pankaj
• 通讯作者: Kapahi, Pankaj