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）的发病和进展中起关键作用，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，JNK在阿尔茨海默病退行性神经元中被激活。JNK在体外被AB激活，并且AB诱导的JNK激活介导AB毒性，这一事实支持了JNK参与AD的神经元变性。然而，鉴于在体内并非所有含有AB增加的神经元都激活JNK，因此AB诱导JNK激活的机制尚不完全清楚，可能涉及其他因素。今后的研究将集中于了解这些额外的因素，这不仅将有助于了解重要的基础生物学过程，而且还将提供新的治疗靶点。先前，我们发现铁与AD的病理标志病变相关，这与AD病例中活化JNK的分布模式相似。此外，我们证明，当用铁螯合剂去铁胺预处理AB时，AB的毒性显著减弱，这表明铁增加了AB的毒性。最重要的是，我们发现JNK在积累铁的Tg2576 ABPP转基因小鼠中被激活，而在不积累铁的Van Leuvan’s ABPP转基因小鼠中则没有被激活。因此，我们假设铁对ab诱导的JNK激活至关重要。此外，由于损伤相关的铁能够参与原位氧化，并容易催化H2O2依赖性氧化，介导AB毒性，我们进一步假设H2O2介导金属增强AB诱导的JNK活化。具体目的如下：目的1和目的2：确定AD患者和ABPP小鼠易感神经元中JNK活化、Ab沉积和铁积累的关系。目的3：确定金属离子螯合对ab诱导的JNK活化的影响。目的4：确定H2O2是否介导金属增强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.