Ca2+/ CaMKII/Tau信号途径在高强度次声波引发神经退行性变及认知功能障碍过程中的机制研究

Infrasound harm and relative action mechanism as well as protection have been highly concerned. High intensity infrasound can induce multiple sites injuries to cerebral cortex, hippocampus, etc. causing neurodegeneration and cognitive dysfunction. It has been shown that over-phosphorylation of Tau protein can interfere with microtubule polymerization, resulting in degeneration and incapacitation of axons, and CaMKII is the key kinase for Tau protein phosphorylation, which can be initiated by calcium overload. Our studies found that high intensity infrasound can significantly increase both the concentration of Ca2+ in hippocampal cells and the level of CaMKII phosphorylation in hippocampus. Therefore we suggested that infrasound might disrupt the steady-state of Ca2+, which causes CaMKII-Tau protein phosphorylation abnormality, and further results in cognitive deficits. This study will use in vivo animal models and in vitro cell models to study the relationship between rat cognitive deficits and the Ca2+-CaMKII-Tau protein phosphorylation pathway with molecular biological technology, etc., in order to provide a theoretical basis for screening out target points for prevention and treatment of infrasound induced brain injuries.

次声危害及其作用机制和防护已受到高度关注。较高强度次声可致大脑皮质、海马等多部位损害，引发神经退行性改变及认知功能障碍。研究表明，Tau蛋白过度磷酸化可引发微管蛋白解聚，造成神经纤维退变及功能丧失，而CaMKⅡ是调控Tau蛋白磷酸化的关键激酶，细胞内钙超载是Tau蛋白异常磷酸化始动因素之一。我们的研究发现较高强度次声作用可致大鼠海马细胞内Ca2+ 浓度显著增高及海马CaMKⅡ磷酸化水平显著上调；据此我们推测，次声可能导致细胞内Ca2+稳态失调后引起CaMKⅡ对Tau蛋白的异常磷酸化，进而导致认知功能受损。然而Ca2+/ CaMKII/Tau信号途径在次声导致神经退行性变及认知功能障碍中是否发挥关键作用及作用机制仍不清楚。因此，本课题拟采用分子生物学等技术研究次声对认知功能损害与Ca2+/ CaMKII/Tau信号途径的相关机制，拟为筛选次声脑损伤药物防治靶点及次声相关病因学提供理论依据。

以往研究表明，较高强度次声暴露可引发神经系统损伤。本课题主要检测了8Hz，130dB次声暴露后大鼠海马区神经元内Ca2+/ CaMKII/Tau信号途径中的关键分子。结果显示，8Hz，130dB次声暴露14天后显著提高了大鼠海马区钙调依赖性蛋白激酶II（pT286-CaMKⅡ）及tau蛋白的表达水平，同时行为学检测表明大鼠学习记忆功能明显降低。经应用钙离子拮抗剂-NMDA受体拮抗剂及RyR受体拮抗剂证实其对次声暴露神经细胞损害具有明显的保护作用，并且能够有效地保护大鼠海马区的神经元及提高损伤后的修复能力，同时行为学实验结果也显示大鼠学习及记忆功能有明显提高。本课题组还利用基因芯片技术筛选出KIF20a、KIF11、NuSAP1、SPAG5等与损伤修复相关性较强的多个基因，为进一步探索次声暴露后神经损伤修复机制提供了新的思路。