Anti-oxidant therapy in Alzheimer's disease

描述(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，目前尚无治愈方法，但十多年来一直有一个中心假说认为氧化应激是导致该疾病的原因之一。AD在死后组织中的特征是存在老年斑，这是由于大脑中淀粉样蛋白(A)多肽的逐渐积累所致；因此，A是治疗阿尔茨海默病的主要治疗靶点。有许多关于抗氧化剂治疗的研究；然而，没有一项研究定量检测AD的特异性贡献。抗氧化剂疗法的临床试验也显示疗效有限。我们的方法提供AD特定氧化应激的定量读数，以优化抗氧化剂治疗。虽然我们已经证明氧化应激是由AD的衰老斑块本身造成的，但很可能其他p物种，如小的可扩散聚集体、低聚物或A？衍生的可扩散配体(ADDL)也是活性氧物种的来源。这项赠款申请建议识别作为氧化应激来源的聚集和可溶A？成分，并使用阿尔茨海默病转基因小鼠模型在体外和体内评估保护活性的抗氧化剂治疗。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衰老斑块的结构和功能进行成像。可以使用高通量平板阅读器分析或多光子荧光相关光谱(PCS)来分析和表征A型低聚物和ADDL的小的可扩散聚集体。抗氧化剂可以测试它们的能力，以减少或防止由这些小的有毒A？物种造成的氧化应激。结合使用，这些实验范例将被用于从传统和替代来源中筛选潜在的抗氧化剂，以系统地评估银杏提取物、维生素E或葡萄籽提取物等化合物是否为治疗阿尔茨海默病的有效抗氧化剂。这一结果将弥合对阿尔茨海默病氧化应激的描述与直接测定天然和合成产品的抗氧化能力之间的差距，这将有望用于治疗阿尔茨海默病患者。

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.