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 衰老和慢性高血糖导致几种代谢和生化扰动 一系列高反应性α-二苯磺酰基化合物的升高（例如，α-DCS，例如甲基乙二醇（MGO）。α-DCS。 是不可避免的副产物，主要是厌氧性糖酵解，它与蛋白质，脂质，脂质，脂质无关反应 和DNA产生一种称为晚期糖基化末端产物（AGES）的异质分子。 大量证据将加速葡萄糖代谢和糖尿病与神经退行性联系起来 阿尔茨海默氏病（AD）等疾病。我们假设葡萄糖代谢的有毒副产品 导致年龄的形成解释了由于高血糖和糖尿病而导致的AD风险增强。支持 在蛋白质聚集体中血清和年龄交联的年龄与增强有关 AD中的神经变性。但是，年龄很难建模，因为它们需要数年的时间才能在人类中积累 它们引起细胞损伤的机制尚待阐明。为了克服这一差距，我们有 建立的秀丽隐杆线虫（蠕虫）模型显着积累了α-DC和年龄，表现出几个年龄 相关的病理，例如对触摸，神经元损伤，瘫痪和早期死亡的高敏性 在成年后的三周内。此外，我们已经观察到直接给药合成 甲基甘氨酸衍生的年龄可以直接引起神经毒性。此外，我们观察到C. 秀丽隐杆线模型过表达了tau的促进形式，这是在阿尔茨海默氏症中暗示的 疾病对饮食中的葡萄糖或年龄敏感。在此提案中，我们将检验假设 葡萄糖和脂质代谢途径的变化，尤其是随着年龄的影响，影响MGO和相关的 年龄，从而导致与AD相关的神经退行性。我们还将通过 老化会影响代谢功能障碍，并导致AD神经退行性。 在AIM 1中，我们将探讨年龄对正常衰老和中神经退行性影响的影响 阿尔茨海默氏病模型使用合成的年龄。我们还将研究与年龄相关的作用 葡萄糖代谢影响MGO和年龄水平并增强神经退行性的变化 在AD模型中。在AIM 2中，我们将确定脂质代谢与年龄产生之间的关系。 我们将一般和物理操纵脂肪酸氧化途径来检查其影响 通过调节年龄调节正常衰老和AD模型中的神经退行性。在目标3中我们 提议确定年龄介导其毒性导致脂肪酸的机制 氧化和神经退行性。我们将确定结合年龄的蛋白质和治疗靶点以调节 与年龄有关的神经退行性。这些研究将确定几个遗传和药物目标 改善年龄并减慢AD中神经退行性的进展。