Anti-oxidant therapy in Alzheimer's disease

阿尔茨海默病的抗氧化治疗

• 批准号: 7032562
• 负责人: Brian J Bacskai
• 金额: $ 27.47万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032562
• 关键词: Alzheimer' s disease; alternative medicine; amyloid proteins; antioxidants; brain disorder chemotherapy; brain morphology; chemical aggregate; drug interactions; drug screening /evaluation; fluorescence microscopy; fluorescence spectrometry; fluorescent dye /probe; genetically modified animals; ginkgo biloba; high throughput technology; laboratory mouse; molecular /cellular imaging; neuritic plaques; neuroprotectants; nonhuman therapy evaluation; oxidative stress; tocopherols

DESCRIPTION (provided by applicant): 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-¿ (A¿) peptides; thus A¿ is the principle therapeutic target for treating Alzheimer's disease. There are numerous studies with anti-oxidant therapy; however none examine the AD-specific contribution quantitatively. Clinical trials with anti-oxidant therapy 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, oligomers, or A¿ derived diffusible ligands (ADDLs) are also a source of reactive oxygen species. This grant application proposes to identify aggregated and soluble A¿ 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 Alzheimer's disease. 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 A¿ 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 A¿ 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.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种毁灭性的神经系统疾病，没有已知的治愈方法，但是中心假设隐式氧化应激作为疾病的原因已有十多年了。 AD在验尸组织中的特征是存在淀粉样蛋白（A e）肽的逐渐脑积累而产生的老年斑块。因此，A是治疗阿尔茨海默氏病的主要治疗靶点。有许多抗氧化治疗的研究。但是，没有定量检查广告特定的贡献。抗氧化治疗的临床试验也显示出有效性有限。我们的方法提供了广告特异性氧化应激的定量读数，以优化抗氧化剂治疗。虽然我们已经表明，氧化应激是由AD本身的老年斑块引起的，但其他P物种（例如，小的扩散骨料，低聚物，低聚物或衍生的扩散配体（ADDL））也可能是活性氧的来源。这项批准应用建议鉴定氧化物胁迫来源的聚合和固体A组分，并使用阿尔茨海默氏病的转基因小鼠模型在体外和体内评估抗氧化剂处理。我们的强度在于基于多光子显微镜的复杂成像技术的利用，该技术使我们能够在体外和体内在结构和功能上对老年斑块进行成像。可以使用高通量板阅读器分析或多光子荧光相关光谱（PCS）来分析和表征A字的小型扩散聚集体。可以测试抗氧化剂的能力，以减少或防止这些小有毒A域产生的氧化应激。结合使用，这些实验范式将用于从传统和替代来源筛选潜在的抗氧化剂，以系统地评估Ginkgo Biloba提取物，维生素E或葡萄种子提取物等化合物是否是阿尔茨海默氏病治疗的有效抗氧化剂。结果将弥合阿尔茨海默氏病中氧化应激的描述，直接确定天然和合成产品的抗氧化能力，这应该有望治疗AD患者。