Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model
Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model
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DOI：
10.1097/01.jnen.0000240468.12543.af
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发表时间：
2006-11-01
影响因子：
3.2
通讯作者：
Bacskai, Brian J.
中科院分区：
文献类型：
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作者：
Garcia-Alloza, Monica;Dodwell, Sarah A.;Bacskai, Brian J.
阿尔茨海默病（AD）的特征是老年斑和神经退行性变，虽然两者之间的关系的细节还没有很好地理解。我们推测，老年斑引起的氧化应激可能介导斑块对局部神经过程的影响。使用多光子显微镜，我们直接证明了老年斑的活性氧的产生。在体外筛选了几种天然抗氧化剂后，我们在体内评估了2种口服抗氧化剂在APPswe/PS1 d9转基因小鼠中的作用。银杏叶提取物和维生素E都降低了体内老年斑引起的氧化应激，如颅内成像所监测的。这两种治疗也导致与老年斑相关的营养不良性神经突的结构变化的进行性逆转。这些结果表明，斑块相关的氧化应激和神经炎性改变之间的因果关系，并首次证明，局灶性神经毒性与老年斑的AD是部分可逆的抗氧化治疗。定量离体筛选结合体内疗效监测应导致更有效的临床治疗，以预防AD的氧化应激和神经毒性。
Alzheimer disease (AD) is characterized both by senile plaques and neurodegeneration, although the details of the relationship between the 2 are not well understood. We postulated that oxidative stress resulting from senile plaques may mediate plaques' effects on local neuronal processes. Using multiphoton microscopy, we directly demonstrate the generation of reactive oxygen species by senile plaques. After screening of several natural antioxidants ex vivo, we assessed in vivo the effect of 2 orally administered antioxidants in APPswe/PS1d9 transgenic mice. Both Ginkgo biloba extract and vitamin E reduced the oxidative stress resulting from senile plaques in vivo as monitored with intracranial imaging. Both treatments also lead to a progressive reversal of the structural changes in dystrophic neurites associated with senile plaques. These results suggest a causal relationship between plaque-associated oxidative stress and neuritic alterations and demonstrate for the first time that the focal neurotoxicity associated with the senile plaques of AD is partially reversible with antioxidant therapies. The quantitative ex vivo screen combined with in vivo monitoring of efficacy should lead to more effective clinical therapies for the prevention of oxidative stress and neurotoxicity in AD.