Oxidation of K+ channels mediates an amyloidogenic pathway common to Alzheimer's disease and TBI

电压门控性钾(K+)通道B亚家族成员1(KCNB1)对氧化还原反应敏感。就其本身而言 该通道的氧化修饰有可能发生在多个 与氧化应激相关的条件。因此，POST中存在氧化的KCNB1通道 老年供体的人死后海马区，且数量明显更多 阿尔茨海默病(AD)捐赠者。KCNB1氧化增加神经元丢失并损害认知功能 AD小鼠模型(3xTg-AD背景)和创伤性脑损伤(TBI)。这两个条件是 与多种病因和致病机制有关，但具有强烈的氧化应激。此外， 与KCNB1通道氧化相关的毒性效应可由FDA批准的药物达沙替尼缓解。这项建议的主要目标是阐明黄曲霉毒素的神经毒性作用的分子基础。 KCNB1氧化。我们将检验两个相应的假设。首先，氧化的KCNB1通道促进了 应激激活蛋白激酶(SAPK)途径的神经毒性。第二，KCNB1介导的 SAPK信号的激活在AD和脑损伤脑中提供了共同的淀粉样变通路，通过 通过直接和/或间接失调b-分泌酶活性来增加b-淀粉样蛋白的产量 (BACE1)。我们将通过遗传学、行为分析、生物化学和 组织化学。如果成功，这项工作将：1)促进我们对一种广泛存在的 神经元易损性；2)阐明AD和脑外伤常见的淀粉样变性的新途径，而不是 之前考虑过的，以及3)可能指示可转化为临床试验的新的治疗方法。

The voltage-gated potassium (K+) channel sub-family B member 1 (KCNB1) is susceptible to redox. As such oxidative modification of this channel has the potential to occur under, and consequently to impact, a number of conditions associated with oxidative stress. Accordingly, oxidized KCNB1 channels are present in the post mortem human hippocampi of aging donors and in significantly larger amounts in the hippocampi of Alzheimer's disease (AD) donors. KCNB1 oxidation increases neuronal loss and impairs cognitive function in mouse models of AD (3xTg-AD background) and traumatic brain injury (TBI). These two conditions are associated with multiple etiologies and pathogenic mechanisms but share robust oxidative stress. Moreover, the toxic effects associated with oxidation of the KCNB1 channels are moderated by Dasatinib, a FDA-approved drug. The broad goal of this proposal is to elucidate the molecular basis for the neurotoxic effects of KCNB1 oxidation. We will test two consequential hypotheses. First, that oxidized KCNB1 channels promote neurotoxicity through the Stress Activated Protein Kinase (SAPK) pathway. Second, that KCNB1-mediated activation of SAPK signaling provides a common amyloidogenic pathway in the AD and the TBI brains, by increasing b-amyloid production via direct and/or indirect dysregulation of the activities of the b-secretase (BACE1). We will test these hypotheses by the means of genetics, behavioral analysis, biochemistry and histochemistry. If successful, this work will: 1) advance our understanding of a widespread mechanism of neuronal vulnerability; 2) elucidate a new pathway for amyloidosis common to AD and TBI, that was not considered before and 3) may indicate novel therapeutic approaches that could be translated into clinical trials.