Role of glyoxalase-1 in Alzheimer's disease pathogenesis and therapy

乙二醛酶-1在阿尔茨海默病发病机制和治疗中的作用

• 批准号: 10393023
• 负责人: Swati S More
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393023
• 关键词: Address; Advanced Glycosylation End Products; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloid deposition; Antioxidants; Attenuated; Brain; Brain region; Catabolism; Cells; Cerebral cortex; Cerebrum; Clinical; Clinical Trials; Cognition; Cognitive deficits; Data; Development; Disease; Disease Progression; Drug Kinetics; Effectiveness; Elderly; Enzymes; Free Radicals; Functional disorder; Future; Gamma-glutamyl transferase; Gastrointestinal tract structure; Generations; Glutathione; Goals; Hippocampus (Brain); Homeostasis; Impaired cognition; In Vitro; Inflammation; Lactoylglutathione Lyase; Lead; Learning; Mediator of activation protein; Metabolic; Metabolism; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oral; Oxidative Stress; Oxides; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Prevalence; Process; Prodrugs; Proteins; Proteolysis; Research; Resistance; Role; Senile Plaques; Sulfhydryl Compounds; Supplementation; Symptoms; System; Tauopathies; Testing; Therapeutic; Toxic effect; Treatment Efficacy; abeta accumulation; abeta deposition; aging brain; amyloid pathology; analog; base; clinical development; extracellular; glycation; hyperphosphorylated tau; improved; innovation; mimetics; molecular targeted therapies; mouse model; neuron loss; neuroprotection; new therapeutic target; novel; novel therapeutics; pre-clinical; preclinical evaluation; preclinical study; prevent; progressive neurodegeneration; prospective; prototype; rational design; restoration; stress reactivity; sugar; tau Proteins; tau aggregation; therapy development; tool

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease responsible for cognitive impairment in elderly subjects. In AD, loss of neurons in the cerebral cortex and hippocampus is accompanied by extracellular deposition of Aβ plaques and neurofibrillary tangles of hyper phosphorylated tau. Currently, other than symptomatic therapies to maintain cerebrocortical activity and to modulate learning/cognition, there are no ways to stop the progression of the disease. Given the increased prevalence of the disease, there is an urgent need to develop therapies that can stop or slow down the progression of AD. Increased oxidative stress is implicated in the onset and progression of AD. Free radicals and reactive dicarbonyls under oxidative stress conditions irreversibly modify proteins forming proteolysis-resistant Advanced Glycation End products (AGEs) and have been implicated as causative agents in AD related cell dysfunction and degeneration. Normally, the Glyoxalase enzyme system (Glo-1), combined with glutathione (GSH), reduces oxidative stress and reactive dicarbonyls responsible for AGE formation. However, reduction in brain GSH levels increases oxidative stress and renders Glo-1 inactive. Unfortunately, GSH supplementation is highly inefficient as GSH is not orally bioavailable and is unstable in plasma due to the efficient catabolism by γ-glutamyl transpeptidase (GGT). To improve the utility of GSH supplementation for AD, we have developed a GSH analog (ψ-GSH) that is resistant to GGT. Our studies show that ψ-GSH accumulates in the brain more efficiently than GSH and protects AD mouse model from onset of AD pathology. In the proposed studies, we will test the hypothesis that the GGT- resistant GSH-mimetic compounds will reduce oxidative stress and AGEs and slow/stop the progression of AD pathology in symptomatic stages of AD mouse models, including progressive neurodegeneration. Second, we aim to determine the role of Glo-1 enzyme system in AD pathogenesis and progression, and determine if Glo-1 enzyme is required for ψ-GSH dependent neuroprotection. Finally, we propose to develop prodrugs of ψ-GSH that will be more bioavailable than ψ-GSH. The results of these studies will form a basis for rational design of druggable Glo-1 substrates and will provide strong justification for their continued development.

项目摘要 阿尔茨海默病（AD）是最常见的进行性神经退行性疾病，其导致认知功能障碍。 老年受试者的损伤。在AD中，伴随着大脑皮层和海马中神经元的损失， 通过Aβ斑块的细胞外沉积和过度磷酸化tau的神经元缠结。目前，其他 比对症治疗，以维持皮层活动和调节学习/认知，没有 阻止疾病发展的方法鉴于这种疾病的流行率增加，迫切需要 需要开发可以阻止或减缓AD进展的疗法。氧化应激增加是 与AD的发病和进展有关。氧化应激下的自由基和反应性二羰基 条件不可逆地修饰形成抗蛋白水解的晚期糖基化终产物（AGEs）的蛋白质 并且已经被认为是AD相关细胞功能障碍和变性的病原体。通常 谷胱甘肽酶系统（Glo-1）与谷胱甘肽（GSH）结合，减少氧化应激和反应性 二羰基负责AGE的形成。然而，脑GSH水平的降低会增加氧化应激， 并使Glo-1失活。不幸的是，GSH补充是非常低效的，因为GSH不是口服的。 由于γ-谷氨酰转肽酶（GGT）的有效催化作用，其在血浆中不稳定。到 为了提高GSH补充剂对AD的效用，我们开发了一种GSH类似物（β-GSH）， 到GGT。我们的研究表明，β-GSH在大脑中的积累比GSH更有效，并保护AD 小鼠模型从AD病理开始。在拟议的研究中，我们将检验GGT- 抗GSH-模拟物化合物将减少氧化应激和AGEs并减缓/停止AD的进展 AD小鼠模型的症状阶段的病理学，包括进行性神经变性。二是 目的探讨Glo-1酶系统在AD发病机制和进展中的作用， 酶是β-GSH依赖性神经保护所必需的。最后，我们建议开发β-GSH的前药 比β-GSH生物利用度更高。这些研究的结果将为合理设计 可药用Glo-1底物，并将为其继续开发提供强有力的理由。