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

K 通道氧化介导阿尔茨海默病和 TBI 常见的淀粉样蛋白生成途径

• 批准号: 10062467
• 负责人: FEDERICO SESTI
• 金额: $ 39.75万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062467
• 关键词: 3xTg-AD mouse; Abeta synthesis; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloidosis; Apoptosis; Behavioral; Biochemistry; Brain; Brain Injuries; Caenorhabditis elegans; Cells; Clinical Treatment; Clinical Trials; Consequentialism; Dasatinib; Disease; Epigenetic Process; Etiology; FDA approved; Failure; Family; Focal Adhesions; Genetic; Goals; Hippocampus (Brain); Histocytochemistry; Homologous Gene; Hour; Human; Impaired cognition; Individual; Integrins; Laboratory Research; Link; MAPK8 gene; Macromolecular Complexes; Mediating; Modification; Molecular; Mus; Names; Neurodegenerative Disorders; Neurons; Oxidation-Reduction; Oxidative Stress; Oxides; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Potassium; Potassium Channel; Process; Production; Proteins; Reactive Oxygen Species; Recording of previous events; Rest; Signal Pathway; Signal Transduction; Testing; Time; Tissues; Toxic effect; Translating; Trauma; Traumatic Brain Injury; Tyrosine; Vertebrates; Voltage-Gated Potassium Channel; Work; aging hippocampus; beta secretase; beta-site APP cleaving enzyme 1; blood-brain barrier permeabilization; cancer therapy; cognitive function; disability; drug efficacy; efficacy testing; experimental study; member; mouse model; nervous system disorder; neuroinflammation; neuron loss; neurotoxic; neurotoxicity; normal aging; novel; novel therapeutic intervention; oxidation; response; sensor; stress activated protein kinase; therapeutic evaluation; tool; voltage

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.

电压门控钾（K+）通道亚家族B成员1（KCNB 1）对氧化还原敏感。因此 该通道的氧化修饰有可能发生，并因此影响， 与氧化应激有关的病症。因此，氧化的KCNB 1通道存在于后 老年捐赠者的尸检人类肾脏， 阿尔茨海默病（AD）供体。KCNB 1氧化增加神经元丢失并损害认知功能 AD（3xTg-AD背景）和创伤性脑损伤（TBI）的小鼠模型。这两个条件 与多种病因和致病机制相关，但共享强大的氧化应激。此外，委员会认为， 与KCNB 1通道氧化相关的毒性作用被FDA批准的药物达沙替尼缓和。这项建议的主要目标是阐明神经毒性作用的分子基础， KCNB 1氧化。我们将检验两个重要的假设。首先，氧化的KCNB 1通道促进 通过应激活化蛋白激酶（SAPK）途径的神经毒性。第二，KCNB 1介导的 SAPK信号传导的激活在AD和TBI脑中提供了共同的淀粉样蛋白生成途径， 通过β-分泌酶活性的直接和/或间接失调增加β-淀粉样蛋白的产生 （BACE 1）。我们将通过遗传学、行为分析、生物化学和 组织化学如果成功的话，这项工作将：1）推进我们对一种广泛的机制的理解， 神经元脆弱性; 2）阐明了AD和TBI共同的淀粉样变性的新途径，这不是 考虑之前和3）可能表明新的治疗方法，可以转化为临床试验。