Anti-oxidant therapy in Alzheimer's disease

阿尔茨海默病的抗氧化治疗

• 批准号: 7794971
• 负责人: Brian J Bacskai
• 金额: $ 25.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7794971
• 关键词: Acute; Advanced Glycosylation End Products; Alzheimer' s Disease; Amyloid; Antioxidants; Apoptosis; Applications Grants; Biological Assay; Brain; Chronic; Clinical Trials; Detection; Disease; Effectiveness; Fluorescence; Fluorescent Probes; Free Radicals; Generations; Ginkgo biloba extract; Gliosis; Image; Imaging Techniques; In Vitro; Life; Ligands; Measures; Mediating; Microscopy; Monitor; Neurologic; Neuronal Dysfunction; Neurons; Outcome Measure; Oxidative Stress; Pathogenesis; Patients; Peptides; Reactive Oxygen Species; Reader; Reporter; Research Personnel; Senile Plaques; Sorting - Cell Movement; Source; Spectrum Analysis; Stress; Structure; Synapses; Techniques; Testing; Tissues; Toxic effect; Transgenic Mice; Vitamin E; antioxidant therapy; base; brain tissue; effective therapy; functional outcomes; grape seed extract; high throughput screening; in vivo; mouse model; oxidation; oxidative damage; peroxidation; prevent; therapeutic target

Alzheimer's disease (AD) is a devastating neurological illness with no known cure, yet a central hypothesis implicating oxidative stress as a cause of the disease has been postulated for more than a decade. AD is characterized in post-mortem tissue by the presence of senile plaques that result from the progressive brain accumulation of amyloid-p (A(3)peptides; thus Ap is the principle therapeutic target for treating AD. There are numerous studies with anti-oxidant therapy, however none examine the AD-specific contribution quantitatively. Clinical trials with anti-oxidant therapy have have also shown limited efficacy. Our approach provides quantitative readouts of AD-specific oxidative stress to optimize an anti-oxidant treatment. While we have shown that oxidative stress results from the senile plaques of AD themselves, it is likely that other p species, such as small diffusible aggregates, oligpmers, or Ap derived diffusible ligands (ADDLs) are also a source of reactive oxygen species. This grant application proposes to identify aggregated and soluble Ap components that are sources of oxidative stress, and evaluate anti-oxidant treatments for protective activity both in vitro and in vivo using transgenic mouse models of AD. Our strength lies in the utilization of. sophisticated imaging techniques based on multiphoton microscopy that allow us to image senile plaques structurally and functionally in vitro and in vivo. Small diffusible aggregates of Ap like oligomers and ADDLs can be analyzed and characterized using high-throughput plate-reader assays or multiphoton fluorescence correlation spectroscopy (PCS). Anti-oxidants can be tested for their ability to reduce or prevent the oxidative stress resulting from these small toxic Ap species. In combination, these experimental paradigms will be used to screen potential anti-oxidants from both traditional and alternative sources to systematically evaluate whether compounds like ginkgo biloba extract, vitamin E, or grape seed extract are effective anti- oxidants for Alzheimer's disease treatment. The results will bridge the gap between the description of oxidative stress in Alzheimer's disease to direct determination of the anti-oxidant ability of natural and synthetic products that should hold promise for treatment of AD patients.

阿尔茨海默氏病（AD）是一种毁灭性的神经系统疾病，目前尚无治愈方法， 涉及氧化应激作为疾病的原因已经被假定了十多年。AD是 在死后的组织中以存在老年斑为特征的，老年斑是由进行性脑损伤引起的 淀粉样蛋白-p（A（3）肽的积累;因此Ap是治疗AD的主要治疗靶点。那里 有许多关于抗氧化剂治疗的研究，但没有一项研究检查AD特异性的作用， 数量上。抗氧化治疗的临床试验也显示出有限的疗效。我们的方法 提供AD特异性氧化应激的定量读数，以优化抗氧化治疗。而 我们已经表明，氧化应激是由老年性痴呆的老年斑本身引起的，很可能是其他因素引起的。 p物质，如小的可扩散聚集体、寡聚体或Ap衍生的可扩散配体（ADDL）也是可扩散的。 活性氧的来源。该拨款申请提议识别聚集的和可溶的Ap 成分是氧化应激的来源，并评估抗氧化治疗的保护活性 使用AD的转基因小鼠模型进行体外和体内研究。我们的优势在于利用。 基于多光子显微镜的先进成像技术， 在体外和体内的结构和功能。Ap样寡聚体和ADDL的小的可扩散聚集体 可以使用高通量读板仪测定或多光子荧光分析和表征 相关光谱（PCS）。抗氧化剂可以测试其减少或防止氧化的能力。 氧化应激导致这些小的有毒Ap物种。综合起来，这些实验范例 将用于筛选潜在的抗氧化剂从传统和替代来源， 评估银杏叶提取物、维生素E或葡萄籽提取物等化合物是否有效抗- 治疗阿尔茨海默病的氧化剂。这些结果将弥合描述之间的差距 阿尔茨海默病中的氧化应激，以直接测定天然和 合成产品，应持有承诺为治疗AD患者。