Anti-oxidant therapy in Alzheimer's disease

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，但仍是一个中心假说 十多年来，人们一直认为氧化应激是导致这种疾病的原因之一。广告是 以死后组织的特征为存在由进行性脑引起的衰老斑块 淀粉样蛋白-P(A(3))积聚；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的特异性贡献 从数量上讲。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特定氧化应激的定量读数，以优化抗氧化剂治疗。而当 我们已经证明，氧化应激是由AD的衰老斑块本身造成的，很可能是其他 磷物种，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 活性氧物种的来源。此授权应用程序建议识别聚合和可分解的AP 作为氧化应激源的成分，并评估抗氧化剂治疗的保护活性 在体外和体内均采用转基因小鼠制作AD模型。我们的优势在于利用。 基于多光子显微镜的复杂成像技术，使我们能够为衰老斑块成像 在体外和体内的结构和功能上。AP样低聚物和ADDL的小而可扩散的聚集体 可以使用高通量平板阅读器分析和表征或多光子荧光 相关光谱(PCS)。抗氧化剂可以测试其减少或防止 这些小的有毒AP物种造成的氧化应激。总而言之，这些实验范式 将用于从传统和替代来源中筛选潜在的抗氧化剂，以系统地 评估银杏叶提取物、维生素E或葡萄籽提取物等化合物是否具有有效的抗肿瘤作用 治疗阿尔茨海默病的氧化剂。结果将弥合描述的差距 氧化应激在阿尔茨海默病中直接测定天然和 有望用于治疗AD患者的合成产品。

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.