Metal Ion is Critical in amyloid beta Induced JNK Activation

Case Western Reserve University, Cleveland OH

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Abstract

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.