Department of Neuroscience and Cell Biology, Rutgers University Robert Wood Johnson Medical School, 683 Hoes Lane West, Piscataway, NJ, 08854, USA.
Cell Death Dis. 2018 Jul 26;9(8):820. doi: 10.1038/s41419-018-0886-1.
Oxidative modification of the voltage-gated K channel subfamily B member 1 (KCNB1, Kv2.1) is emerging as a mechanism of neuronal vulnerability potentially capable of affecting multiple conditions associated with oxidative stress, from normal aging to neurodegenerative disease. In this study we report that oxidation of KCNB1 channels is exacerbated in the post mortem brains of Alzheimer's disease (AD) donors compared to age-matched controls. In addition, phosphorylation of Focal Adhesion kinases (FAK) and Src tyrosine kinases, two key signaling steps that follow KCNB1 oxidation, is also strengthened in AD vs. control brains. Quadruple transgenic mice expressing a non-oxidizable form of KCNB1 in the 3xTg-AD background (APP, PS1, and tau), exhibit improved working memory along with reduced brain inflammation, protein carbonylation and intraneuronal β-amyloid (Aβ) compared to 3xTg-AD mice or mice expressing the wild type (WT) KCNB1 channel. We conclude that oxidation of KCNB1 channels is a mechanism of neuronal vulnerability that is pervasive in the vertebrate brain.
电压门控钾通道亚家族 B 成员 1（KCNB1，Kv2.1）的氧化修饰作为一种神经元易损性的机制正在出现，这种机制可能会影响与氧化应激相关的多种情况，从正常衰老到神经退行性疾病。在这项研究中，我们报告称，与年龄匹配的对照组相比，阿尔茨海默病（AD）供体的死后大脑中 KCNB1 通道的氧化作用加剧。此外，与对照组大脑相比，FAK 和Src 酪氨酸激酶的磷酸化（紧随 KCNB1 氧化之后的两个关键信号步骤）在 AD 中也得到了加强。在 3xTg-AD 背景（APP、PS1 和 tau）中表达不可氧化形式的 KCNB1 的四重转基因小鼠，与 3xTg-AD 小鼠或表达野生型（WT）KCNB1 通道的小鼠相比，表现出改善的工作记忆以及减少的脑炎症、蛋白羰基化和神经元内β-淀粉样蛋白（Aβ）。我们得出结论，KCNB1 通道的氧化是神经元易损性的一种机制，在脊椎动物大脑中普遍存在。
