Metal Ion is Critical in amyloid beta Induced JNK Activation

描述(由申请人提供)：由于Abeta(AB)似乎在阿尔茨海默病(AD)的发生和发展中发挥关键作用，了解AB损伤和杀死神经元的途径有可能确定治疗的分子靶点。我们和其他人已经证明，在AD的变性神经元中，JNK被激活。在阿尔茨海默病中，JNK被AB激活，并且AB诱导的JNK激活介导了AB毒性，这支持了JNK参与AD神经元退行性变的事实。然而，由于在活体内并不是所有AB含量增加的神经元都激活了JNK，AB诱导JNK激活的机制仍不完全清楚，其他因素(S)显然参与其中。拟议的研究将集中于了解这些附加因子(S)，这不仅将获得一个重要的基本生物学过程的欣赏，而且还将提供新的治疗靶点(S)。此前，我们发现铁与AD的病理标志性病变有关，这与AD病例中激活的JNK的分布模式相似。此外，我们还证明，用铁络合剂去铁胺处理AB时，AB的毒性显著减弱，这表明铁增强了AB的毒性。最重要的是，我们发现JNK在Tg2576 ABPP转基因小鼠中被激活，但在Van Leuvan的ABPP转基因小鼠中没有激活。因此，我们假设铁在AB诱导的JNK激活中起关键作用。此外，由于病变相关的铁能够参与原位氧化，并容易催化依赖H_2O_2的氧化，从而介导AB毒性，我们进一步假设H_2O_2介导了金属增强的AB诱导的JNK激活。具体目标如下：目标1和目标2：确定AD患者和ABPP小鼠易感神经元中JNK激活、抗体沉积与铁蓄积的关系。目的：研究金属离子络合对抗体诱导的JNK活化的影响。目的4：确定H_2O_2是否介导金属增强的AB诱导的JNK活化。

DESCRIPTION (provided by applicant): Since Abeta (AB) appears to play a key role in the onset and progression of Alzheimer's disease (AD), understanding the pathway by which AB injures and kills neurons has the potential to identify molecular targets for therapies. We and others have demonstrated that JNK is activated in degenerating neurons in AD. That JNK is involved in neuronal degeneration in AD is supported by the fact that JNK is activated by AB in vjtro and AB-induced JNK activation mediates AB toxicity. However, given that JNK is not activated in all neurons containing increased AB in vivo, the mechanism of AB-induced JNK activation is still not fully understood and other factor(s) are clearly involved. The proposed studies will focus on understanding these additional factor(s) which will not only gain an appreciation for an important basic biological process, but also provide novel therapeutic target(s). Previously, we identified that iron is associated with the pathological hallmark lesions of AD, which is similar to the distribution pattern of activated JNK in AD case. Further, we demonstrated that AB toxicity is significantly attenuated when AB is pretreated with the iron chelator deferoxamine, suggesting that iron augments AB toxicity. Most importantly, we found that JNK is activated in Tg2576 ABPP transgenic mice which accumulate iron but not in Van Leuvan's ABPP transgenic mice which do not accumulate iron. Therefore, we hypothesize that iron is critical for AB-induced JNK activation. Additionally, since lesion-associated iron is able to participate in in situ oxidation and readily catalyzes an H2O2-dependent oxidation that mediates AB toxicity, we further hypothesize that H2O2 mediates metal-augmented AB-induced JNK activation. The specific goals are as follows: Aim 1 and 2: Determine the relationship between JNK activation, Ab deposition and iron accumulation in susceptible neurons in AD patients and ABPP mice. Aim 3: Determine the effect of metal ion chelation on Ab-induced JNK activation. Aim 4: Determine whether H2O2 mediates metal-augmented AB-induced JNK activation.