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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.

项目概要阿尔茨海默病 (AD) 是最常见的进行性神经退行性疾病，与认知能力相关老年受试者的损伤。在AD中，大脑皮层和海马体中的神经元损失伴随着通过 Aβ 斑块和过度磷酸化 tau 神经原纤维缠结的细胞外沉积。目前，其他除了维持大脑皮质活动和调节学习/认知的对症治疗之外，没有其他方法阻止疾病进展的方法。鉴于该病患病率的增加，迫切需要解决需要开发能够阻止或减缓 AD 进展的疗法。氧化应激增加是与 AD 的发生和进展有关。氧化应激下的自由基和活性二羰基条件不可逆地改变蛋白质，形成抗蛋白水解的高级糖基化终产物 (AGE) 并被认为是 AD 相关细胞功能障碍和退化的致病因素。通常情况下，乙二醛酶系统 (Glo-1) 与谷胱甘肽 (GSH) 结合，可减少氧化应激和反应性二羰基负责 AGE 的形成。然而，大脑谷胱甘肽水平的降低会增加氧化应激并使 Glo-1 失活。不幸的是，谷胱甘肽补充剂的效率非常低，因为谷胱甘肽不是口服的。具有生物利用度，但由于 γ-谷氨酰转肽酶 (GGT) 的有效分解代谢，在血浆中不稳定。到为了提高 GSH 补充剂对 AD 的效用，我们开发了一种具有抗药性的 GSH 类似物 (ψ-GSH) 至 GGT。我们的研究表明 ψ-GSH 比 GSH 更有效地在大脑中积聚并保护 AD AD病理发作时的小鼠模型。在拟议的研究中，我们将检验以下假设：GGT- 抗性 GSH 模拟化合物将减少氧化应激和 AGE，并减缓/阻止 AD 的进展 AD小鼠模型症状阶段的病理学，包括进行性神经变性。第二，我们旨在确定 Glo-1 酶系统在 AD 发病机制和进展中的作用，并确定 Glo-1 是否 ψ-GSH 依赖性神经保护需要酶。最后，我们建议开发ψ-GSH的前药比 ψ-GSH 具有更高的生物利用度。这些研究的结果将为合理设计奠定基础。可药物化的 Glo-1 底物，并将为其持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.