Metal Ion is Critical in amyloid beta Induced JNK Activation

金属离子对于 β 淀粉样蛋白诱导的 JNK 激活至关重要

基本信息

  • 批准号:
    7250071
  • 负责人:
  • 金额:
    $ 24.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-07-01 至 2010-06-30
  • 项目状态:
    已结题

项目摘要

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.
描述(由申请人提供):由于Abeta(AB)似乎在阿尔茨海默病(AD)的发作和进展中起关键作用,因此了解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AD的退化神经元中被激活。JNK参与AD中的神经元变性的事实得到以下事实的支持:JNK在vjtro中被AB激活,并且AB诱导的JNK激活介导AB毒性。然而,考虑到JNK在体内含有增加的AB的所有神经元中未被激活,AB诱导的JNK激活的机制仍未完全理解,并且清楚地涉及其他因子。拟议的研究将侧重于了解这些额外的因素,这不仅将获得对重要的基本生物学过程的理解,而且还将提供新的治疗靶点。以前,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,我们证明,AB毒性显着衰减时,AB与铁螯合剂去铁胺预处理,表明铁增强AB毒性。最重要的是,我们发现JNK在积累铁的Tg 2576 ABPP转基因小鼠中被激活,而在不积累铁的货车Leu货车的ABPP转基因小鼠中没有。因此,我们假设铁对AB诱导的JNK激活至关重要。此外,由于病变相关的铁能够参与原位氧化,并容易催化介导AB毒性的H2O2依赖性氧化,我们进一步假设H2O2介导金属增强的AB诱导的JNK激活。具体目标如下:目的1和2:确定AD患者和ABPP小鼠易感神经元中JNK激活、Ab沉积和铁蓄积之间的关系。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是否介导金属增强的AB诱导的JNK活化。

项目成果

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Xiongwei Zhu其他文献

Xiongwei Zhu的其他文献

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{{ truncateString('Xiongwei Zhu', 18)}}的其他基金

Role of Mettl3-dependent RNA m6A dysregulation in Alzheimer's disease
Mettl3 依赖性 RNA m6A 失调在阿尔茨海默病中的作用
  • 批准号:
    10739065
  • 财政年份:
    2023
  • 资助金额:
    $ 24.6万
  • 项目类别:
Research Education Component
研究教育部分
  • 批准号:
    10474608
  • 财政年份:
    2021
  • 资助金额:
    $ 24.6万
  • 项目类别:
Research Education Component
研究教育部分
  • 批准号:
    10675675
  • 财政年份:
    2021
  • 资助金额:
    $ 24.6万
  • 项目类别:
Research Education Component
研究教育部分
  • 批准号:
    10263716
  • 财政年份:
    2021
  • 资助金额:
    $ 24.6万
  • 项目类别:
Epigenomic Mechanism of Parkinson's Disease
帕金森病的表观基因组机制
  • 批准号:
    8738730
  • 财政年份:
    2013
  • 资助金额:
    $ 24.6万
  • 项目类别:
Epigenomic Mechanism of Parkinson's Disease
帕金森病的表观基因组机制
  • 批准号:
    8547489
  • 财政年份:
    2013
  • 资助金额:
    $ 24.6万
  • 项目类别:
Abnormal Mitochondrial Dynamics and Mitochondrial Dysfunction in Alzheimer's Dise
阿尔茨海默病中的线粒体动力学异常和线粒体功能障碍
  • 批准号:
    9261605
  • 财政年份:
    2013
  • 资助金额:
    $ 24.6万
  • 项目类别:
Training in Neurodegenerative Diseases
神经退行性疾病培训
  • 批准号:
    10614554
  • 财政年份:
    2013
  • 资助金额:
    $ 24.6万
  • 项目类别:
Abnormal Mitochondrial Dynamics and Mitochondrial Dysfunction in Alzheimer's Dise
阿尔茨海默病中的线粒体动力学异常和线粒体功能障碍
  • 批准号:
    8829930
  • 财政年份:
    2013
  • 资助金额:
    $ 24.6万
  • 项目类别:
Training in Neurodegenerative Diseases
神经退行性疾病培训
  • 批准号:
    8869054
  • 财政年份:
    2013
  • 资助金额:
    $ 24.6万
  • 项目类别:

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