Oxidation of cysteine-proteases in Alzheimer's Disease

阿尔茨海默病中半胱氨酸蛋白酶的氧化

• 批准号: 7270125
• 负责人: RODNEY P GUTTMANN
• 金额: $ 15.11万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7270125
• 关键词: Active Sites; Address; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Antioxidants; Area; Attention; Brain; Calcium; Calpain; Cell Death; Cerebellum; Condition; Conflict (Psychology); Cultured Cells; Cysteine; Cysteine Protease; Data; Dementia; Disease; Disease Progression; Emotional; Endopeptidases; Foundations; Functional disorder; Future; Hippocampus (Brain); In Vitro; Individual; Kentucky; Knowledge; Link; Measures; Neurodegenerative Disorders; Oxidants; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Peptide Hydrolases; Predisposition; Protease Inhibitor; Published Comment; Publishing; Regulation; Research; Research Personnel; Research Project Grants; Role; Sampling; Societies; Staging; Sulfhydryl Compounds; Testing; Therapeutic; Thinking; Thiol Proteinases; Time; Universities; Work; abeta accumulation; base; experience; innovation; oxidation; tau Proteins

DESCRIPTION (provided by applicant): Alzheimer's disease is the most common cause of dementia affecting nearly 18 million people worldwide and projected to double over the next 20 years. Without new and significant preventative or curative measures this growing problem will place a substantial burden on society in terms of both financial and emotional strains. Previous research has implicated over activation of thiol-proteases in AD progression. This is based primarily on the observation of an increased 'activation' state of various thiol-proteases in AD brain. However, other data suggest that thiol-proteases are not fully proteolytically active and that inhibition of thiol-proteases is more likely to contribute to AD pathology. Thus, there is an important discrepancy between the observed activation of thiol-proteases and their proteolytic activity in Alzheimer's disease. These contradictory findings regarding thiol-protease 'activation1 and thiol-protease 'activity' need to be resolved in order to move forward and determine the role of thiol-proteases in tau and Abeta accumulation as well as cell death/ dysfunction during Alzheimer's disease. To address this gap in our knowledge we will test the hypothesis that the 'activated' thiol-proteases are oxidatively inhibited at their active-site cysteines by specific oxidants in the hippocampus of Alzheimer's disease. Aim 1: Determine the activity of thiol-dependent proteases in Alzheimer's disease brain compared to age-matched controls within the vulnerable hippocampus and the non-vulnerable cerebellum. Based on our recently published work, we will show that thiol-protease activity, including calcium-dependent thiol-protease activity, is oxidatively inhibited in the hippocampus of AD brain compared to age-matched controls. Because AD degeneration is progressive, we will also determine the extent of thiol-protease oxidation over the progression of the disease using brain samples from various stages of Alzheimer's disease. Aim 2: Determine the oxidants responsible for thiol-protease oxidation in the hippocampus of AD brain. These studies will determine the extent of oxidation and the oxidants responsible for oxidation of active-site cysteines within individual thiol- dependent proteases in AD hippocampus. This hypothesis challenges an existing paradigm by suggesting thiol-protease activity in Alzheimer's disease is decreased (rather than increased) due to oxidation of the active site. The proposed research will have impact on future therapeutics involving anti-oxidant or protease inhibitor strategies in the treatment or prevention of Alzheimer's disease.

描述（由申请人提供）：阿尔茨海默氏病是痴呆症的最常见原因，影响全球近 1800 万人，预计在未来 20 年内这一数字将增加一倍。如果没有新的、重要的预防或治疗措施，这一日益严重的问题将给社会带来巨大的经济和情感压力。先前的研究表明硫醇蛋白酶的过度激活与 AD 的进展有关。这主要基于对 AD 脑中各种硫醇蛋白酶“激活”状态增加的观察。然而，其他数据表明，硫醇蛋白酶不具有完全的蛋白水解活性，并且硫醇蛋白酶的抑制更有可能导致 AD 病理。因此，在阿尔茨海默病中观察到的硫醇蛋白酶的激活与其蛋白水解活性之间存在重要差异。需要解决这些关于硫醇蛋白酶“激活”和硫醇蛋白酶“活性”的矛盾发现，以便进一步确定硫醇蛋白酶在 tau 和 Abeta 积累以及阿尔茨海默病期间细胞死亡/功能障碍中的作用。为了解决我们知识上的这一空白，我们将测试以下假设：“激活的”硫醇蛋白酶在其活性位点半胱氨酸上被阿尔茨海默病海马中的特定氧化剂氧化抑制。目标 1：确定阿尔茨海默病大脑中硫醇依赖性蛋白酶的活性，并与脆弱海马和非脆弱小脑内年龄匹配的对照进行比较。根据我们最近发表的工作，我们将证明与年龄匹配的对照组相比，AD 大脑海马中的硫醇蛋白酶活性（包括钙依赖性硫醇蛋白酶活性）受到氧化抑制。由于 AD 退化是进行性的，我们还将使用阿尔茨海默氏病不同阶段的大脑样本来确定疾病进展过程中硫醇蛋白酶氧化的程度。目标 2：确定 AD 大脑海马中负责硫醇蛋白酶氧化的氧化剂。这些研究将确定氧化程度以及负责 AD 海马中各个硫醇依赖性蛋白酶内活性位点半胱氨酸氧化的氧化剂。这一假说挑战了现有的范式，表明阿尔茨海默病中的硫醇蛋白酶活性由于活性位点的氧化而降低（而不是增加）。拟议的研究将对未来涉及治疗或预防阿尔茨海默病的抗氧化剂或蛋白酶抑制剂策略的疗法产生影响。