Processing Of Oxidative Stress In Alzheimer

我们正在利用多个模型系统如转基因小鼠、培养细胞和C.优雅我们专注于阿尔茨海默病（AD），因为这是65岁或以上人群中最常见的痴呆症。碱基切除修复（BER）途径修复氧化性DNA损伤，如碱基修饰，其自发发生或由活性氧（ROS）攻击。DNA聚合酶β（PolB）负责BER途径中的DNA合成步骤，这可能是限速的。 我们观察到AD患者中PolB的表达降低，因此我们将3xTg AD小鼠与我们的DNA聚合酶β杂合小鼠（PolB）交配以创建新的小鼠模型，3xTgAD/PolB+/-。这种新的AD品系显示出亲本AD小鼠模型没有的几个重要的新特征。我们观察到细胞死亡标志物升高，ABeta沉积改变，线粒体功能障碍加重，记忆力、学习和嗅觉缺陷恶化。这些增加的功能使新的小鼠模型更类似于在人类中看到的AD表现。总之，我们的工作和其他人的工作表明，BER酶的缺乏可能有助于AD患者的核和线粒体DNA中氧化损伤的积累，并有助于疾病的进展。 在我们的3xTg/PolB模型中，我们已经表明NAD补充使关键AD特征如磷酸化tau、记忆和学习缺陷正常化。在某种程度上，我们认为这是由于DNA修复的增加和线粒体功能和线粒体自噬的改善。我们已经表明，人类AD患者的脑细胞和培养的神经元显示线粒体功能障碍。因此，我们试图评估线粒体自噬增强剂如NAD补充剂、尿石素A或放线菌素是否也可以改善AD模型中的AD特征。在这里，我们使用APP/PS1小鼠和A或tau C。elegans AD models.线粒体自噬刺激剂在改善蠕虫和小鼠的记忆方面是有效的。重要的是，我们观察到增加的吞噬活性的小胶质细胞和减少神经炎症APP/PS1小鼠后，尿石素A或放线菌素。我们之前在3xTgAD小鼠中观察到了NAD补充的类似结果。在tau过表达的人神经元细胞和3xTgAD小鼠中，线粒体自噬诱导特异性地减少了过度磷酸化tau的出现，过度磷酸化tau是AD病理学的主要标志物。在这些结果的鼓舞下，我们将继续描述AD模型和其他神经退行性疾病中线粒体自噬诱导的益处。

We are testing the hypothesis that the accumulation of oxidative DNA damage contributes to neuronal dysfunction seen in neurodegenerative diseases by utilizing multiple model systems like transgenic mice, cultured cells and C. elegans. We are focusing on Alzheimer's disease (AD) since this is the most prevalent form of dementia in people 65 years or older. The base excision repair (BER) pathway repairs oxidative DNA damage, such as base modifications, which occur spontaneously or from attack by reactive oxygen species (ROS). DNA polymerase Beta (PolB) is responsible for the DNA synthesis step in the BER pathway, which can be rate limiting. We observed decreased expression of PolB in AD patients so we bred the 3xTg AD mouse to our DNA Polymerase Beta heterozygous mouse (PolB) to create a new mouse model, 3xTgAD/PolB+/-. This new AD strain displayed several important new features that the parental AD mouse model did not. We observed elevated cell death markers, altered ABeta deposition, greater mitochondrial dysfunction, worse memory, learning, and smelling defects. These added features make the new mouse model more similar to the AD presentation seen in humans. Together, our work and others suggest that deficiencies in BER enzymes might contribute to the accumulation of oxidative damage in both nuclear and mitochondria DNA of AD patients and contribute to disease progression. In our 3xTg/PolB model, we have shown that NAD supplementation normalized key AD features like phospho-tau, memory and learning deficits. In part, we believed this is due to increased DNA repair and improved mitochondrial function and mitophagy. We have shown that human AD patient brain cells and cultured neurons display mitochondrial disfunction. Thus, we sought to evaluate whether mitophagy enhancers like NAD supplementation, urolithin A or actinonin could also improve AD features in AD models. Here we used APP/PS1 mice and A or tau C. elegans AD models. Mitophagy stimulators were effective at improving memory in worms and mice. Importantly, we observed increased phagocytic activity of microglia and reduced neuroinflammation in APP/PS1 mice following administration of urolithin A or actinonin. We had previously observed similar findings with NAD supplementation in 3xTgAD mice. In both tau overexpressing human neuronal cells and 3xTgAD mice, mitophagy induction specifically decreased the appearance of hyperphosphorylated tau, a major marker of AD pathology. Encouraged by these results we are continuing to characterize the benefits of mitophagy induction in AD models and other neurodegenerative diseases.