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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

基本信息

批准号：
10614421
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614421
关键词：
Address Advanced Glycosylation End Products Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Amyloid deposition Antioxidants Attenuated Biological Availability Brain Brain region Catabolism Cells Cerebral cortex Cerebrum Clinical Clinical Trials Cognition Cognitive deficits Data Development Disease Disease Progression Drug Kinetics Drug Metabolic Detoxication Effectiveness Elderly Enzymes Free Radicals Functional disorder Future Gamma-glutamyl transferase Gastrointestinal tract structure Generations Glutathione Glutathione Metabolism Pathway Goals Hippocampus Homeostasis Impaired cognition In Vitro Inflammation Lactoylglutathione Lyase Lead Learning Mediator Metabolic Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oral Oxidative Stress 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 clinical development extracellular glutathione analog glycation improved innovation mimetics molecular targeted therapies mouse model neuron loss neuropathology neuroprotection new therapeutic target novel novel therapeutics pre-clinical preclinical evaluation preclinical study prevent progressive neurodegeneration prospective prototype rational design restoration sugar tau Proteins tau aggregation tau-1 therapy development tool

项目摘要

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.

项目总结阿尔茨海默病(AD)是导致认知障碍的最常见的进行性神经退行性疾病老年受试者的功能障碍。在AD中，伴随着大脑皮层和海马区神经元的丢失通过细胞外沉积Aβ斑块和过度磷酸化的tau的神经纤维缠结。目前，其他除了对症治疗来维持大脑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程度越来越高，有一个紧迫的问题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的发生和发展有关。氧化应激下的自由基和反应性二羰基形成抗蛋白水解性晚期糖基化终产物(AGEs)的条件不可逆地改变蛋白质并被认为是AD相关细胞功能障碍和变性的致病因素。通常情况下，乙二醇酶系统(Glo-1)与谷胱甘肽(GSH)相结合，可减少氧化应激和反应负责年龄形成的二羰基化合物。然而，大脑GSH水平的降低会增加氧化应激并使Glo-1处于非活动状态。不幸的是，补充GSH的效率非常低，因为GSH不是口服的由于γ-谷氨酰转肽酶(GGT)的高效分解代谢，在血浆中是生物利用的和不稳定的。至为了提高补充谷胱甘肽治疗阿尔茨海默病的有效性，我们开发了一种抗病的谷胱甘肽类似物(ψ-GSH) 致GGT。我们的研究表明，ψ-谷胱甘肽比谷胱甘肽更有效地在大脑中积聚，并保护AD 从阿尔茨海默病小鼠模型的发病病理。在拟议的研究中，我们将检验GGT- 抗GSH类似物将减少氧化应激和AGEs，并减缓/阻止AD的进展阿尔茨海默病小鼠模型症状阶段的病理学，包括进行性神经变性。第二，我们目的探讨Glo-1酶系统在阿尔茨海默病(AD)发生、发展中的作用，以及Glo-1在AD发病机制中的作用。酶是ψ-谷胱甘肽依赖性神经保护所必需的。最后，我们建议开发ψ-谷胱甘肽前药。这将比ψ-GSH更具生物利用度。这些研究的结果将成为合理设计的基础。可药物Glo-1底物，并将为其继续开发提供强有力的理由。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sulfur-containing therapeutics in the treatment of Alzheimer's disease.

DOI：
10.1007/s00044-020-02687-1
发表时间：
2021-03
期刊：
Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents
影响因子：
0
作者：
Zhu H;Dronamraju V;Xie W;More SS
通讯作者：
More SS

Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer's Disease Mouse Model.

DOI：
10.3390/antiox11061075
发表时间：
2022-05-28
期刊：
ANTIOXIDANTS
影响因子：
7
作者：
Raza, Abbas;Xie, Wei;Kim, Kwan-Hyun;Dronamraju, Venkateshwara Rao;Williams, Jessica;Vince, Robert;More, Swati S.
通讯作者：
More, Swati S.

Role of 3-Mercaptopyruvate Sulfurtransferase (3-MST) in Physiology and Disease.

DOI：
10.3390/antiox12030603
发表时间：
2023-03-01
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
通讯作者：

Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo.

DOI：
10.1016/j.redox.2022.102484
发表时间：
2022-11
期刊：
REDOX BIOLOGY
影响因子：
11.4
作者：
Rao, Swetha Pavani;Xie, Wei;Kwon, Ye In Christopher;Juckel, Nicholas;Xie, Jiashu;Dronamraju, Venkateshwara Rao;Vince, Robert;Lee, Michael K.;More, Swati S.
通讯作者：
More, Swati S.