Anti-oxidant therapy in Alzheimer's disease

阿尔茨海默病的抗氧化治疗

• 批准号: 7185057
• 负责人: Brian J Bacskai
• 金额: $ 26.67万
• 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/7185057
• 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; Personal Satisfaction; Reactive Oxygen Species; Reader; Reporter; Research Personnel; Senile Plaques; Sorting - Cell Movement; Source; Spectrum Analysis; Stress; Structure; Synapses; Techniques; Testing; Tissues; Toxic effect; Transgenic Organisms; Vitamin E; base; brain tissue; functional outcomes; grape seed extract; high throughput screening; in vivo; mouse model; oxidation; peroxidation; prevent; size; therapeutic target

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（由申请人提供）：阿尔茨海默病（AD）是一种毁灭性的神经系统疾病，目前还没有已知的治疗方法，然而一个中心假设暗示氧化应激是该疾病的原因，已经假设了十多年。阿尔茨海默病在死后组织中表现为老年斑的存在，老年斑是由淀粉样蛋白- (A)肽的大脑进行性积累引起的；因此A¿是治疗阿尔茨海默病的主要治疗靶点。有很多关于抗氧化疗法的研究；然而，没有人对ad的具体贡献进行定量研究。抗氧化疗法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。虽然我们已经证明氧化应激是由AD老年斑本身引起的，但其他p物质，如小扩散聚集体、低聚物或A衍生物扩散配体（ADDLs）也可能是活性氧的来源。这项拨款申请旨在鉴定氧化应激来源的聚集性和可溶性A¿成分，并利用阿尔茨海默病转基因小鼠模型评估抗氧化治疗在体外和体内的保护活性。我们的优势在于利用基于多光子显微镜的复杂成像技术，使我们能够在体外和体内对老年斑进行结构和功能成像。类A低聚物和addl的小扩散聚集体可以使用高通量平板阅读器测定或多光子荧光相关光谱（PCS）进行分析和表征。抗氧化剂可以测试其减少或防止这些小有毒物质引起的氧化应激的能力。综上所述，这些实验范例将用于筛选来自传统和替代来源的潜在抗氧化剂，以系统地评估像银杏叶提取物、维生素E或葡萄籽提取物这样的化合物是否有效地抗氧化剂用于治疗阿尔茨海默病。这一结果将弥合阿尔茨海默病氧化应激描述与直接确定天然和合成产品抗氧化能力之间的差距，这些产品有望用于治疗阿尔茨海默病患者。