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: 10213648
• 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/10213648
• 关键词: 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; Chemicals; 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; Ketone Bodies; Lactoylglutathione Lyase; Link; Lipids; Longevity; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Obesity; Paralysed; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Play; 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; crosslink; diabetic; fatty acid oxidation; feeding; glucose metabolism; lipid metabolism; mortality; mutant; neurotoxicity; new therapeutic target; normal aging; overexpression; 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.

项目摘要/摘要 衰老和慢性高血糖会导致几种代谢和生化紊乱，包括 一系列高活性的α-二羰基化合物(α-DC)的含量上升，例如甲基乙二醛(MGO)。α-DC 是不可避免的副产品，主要是厌氧糖酵解，不分青红皂白地与蛋白质，脂肪， 和DNA产生一组不同的分子，称为晚期糖基化终产物(AGEs)。一个 大量证据表明，葡萄糖代谢加速和糖尿病与神经退行性变有关 像阿尔茨海默病(AD)这样的疾病。我们假设葡萄糖代谢的有毒副产物 结果AGEs的形成解释了高血糖和糖尿病导致AD风险增加的原因。在支持中 其中，血清中的AGEs和蛋白质聚集体中的AGE交联与增强有关 阿尔茨海默病的神经退行性变。然而，年龄很难建模，因为它们需要多年在人类体内积累和 它们引起细胞损伤的机制仍有待阐明。为了克服这一差距，我们有 已建立的线虫(蠕虫)模型显著积累α-DC和AGE，表现为几个年龄- 相关的病理，如触摸过敏、神经元损伤、瘫痪和早期死亡，都是 在成年后的三周内。此外，我们还观察到，直接给药合成 甲基乙二醛衍生的AGEs可直接导致神经毒性。此外，我们还观察到C。 雅致模型过度表达促聚集形式的tau，这与阿尔茨海默氏症有关 疾病，对饮食中的葡萄糖或AGEs敏感。在这个提案中，我们将检验这一假设 糖脂代谢途径的改变，特别是随着年龄的增加，会影响MGO和相关的 年龄，从而导致与阿尔茨海默病相关的神经变性。我们还将通过以下方式确定机制 哪些年龄影响代谢功能障碍，并导致AD的神经退行性变。 在目标1中，我们将探索AGEs对正常衰老和 使用人工衍生的AGEs建立阿尔茨海默病模型。我们还将研究与年龄相关的 糖代谢变化在影响MGO和AGEs水平及促进神经退行性变中的作用 在AD的模型中。在目标2中，我们将确定脂代谢与AGEs产生之间的关系。 我们将从遗传学和药理学的角度操纵脂肪酸氧化途径，以检验它们的影响。 通过调节AGEs来调节正常衰老和AD模型的神经退行性变。在《目标3》中我们 建议确定AGEs介导其毒性导致脂肪酸抑制的机制 氧化和神经变性。我们将确定年龄结合蛋白和治疗靶点来调节 年龄相关性神经退行性变。这些研究将确定几个遗传和药理学目标，以 改善年龄，延缓阿尔茨海默病的神经退变进程。