Nav1.6在阿尔茨海默病神经网络异常中的作用及机制

Aberrant neural network activity in Alzheimer disease (AD) might contribute to AD-related cognitive decline, but the mechanism of neural network dysfunction is still unclear. Recent studies demonstrated that Levetiracetam (LEV), an anti-epileptic drug, could suppress neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. However, not all anti-epileptic drugs could improve the learning and memory of AD, and this may be related to the different mechanisms of aberrant neural network. Our previous studies revealed the colocalization of amyloid precursor protein （APP, the β-amyloid metabolic precursor） and Nav1.6, and both APP and β-amyloid （Aβ） could increase the current of Nav1.6, thus increase the excitability of neurons. The sodium channel blocker, Lamotrigine (LTG), could attenuate deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice [Neurobiol Aging 2014; 35(12): 2713], indicating that AD-related cognitive decline may be greatly related to the Nav1.6 in the abnormal neural network. Based on previous studies, this project aims to explore the functions and mechanisms regarding the Nav1.6 in the abnormal neural network in APP/PS1 transgenic mice and the correlation between Aβ and cognitive decline, through knockdown the expression of Nav1.6 in hippocampus. Thus we could further investigate the pathophysiology of AD, and provide new strategies for AD treatments.

阿尔茨海默病(AD)脑内神经网络超兴奋被认为是认知功能障碍的重要原因，但异常兴奋机制不清。最近研究表明,抗癫痫药左乙拉西坦能抑制AD鼠神经超兴奋,改善认知障碍。但非所有抗癫痫药都能改善AD学习记忆,可能网络异常机制不同。我们前期研究发现Aβ代谢前体APP和钠通道(Nav)1.6亚型共定位；APP及Aβ均能增加钠电流,提高神经元兴奋性；钠通道阻断剂拉莫三嗪亦可改善AD鼠学习记忆[Neurobiol Aging 2014],提示Nav1.6与AD中异常兴奋的神经网络及由此引发的认知障碍密切相关。本项目拟在前期研究基础上, 以APP/PS1转基因鼠为AD模型, 利用Nav1.6条件敲除鼠与其杂交产生Nav1.6敲除的AD模型鼠或siRNA减低其海马Nav1.6表达,深入研究Nav1.6在AD异常网络兴奋中的作用及与Aβ和认知功能障碍的相关性,以期进一步认识AD发生发展机制,为AD治疗提供新靶点。

神经元网络兴奋性的异常增加可能会导致阿尔兹海默病患者的认知功能障碍。但神经元网络兴奋性异常增加的机制尚不完全清楚。我们之前的研究发现，人类淀粉样蛋白前体蛋白(APP)/早老素1(PS1)转基因小鼠脑内神经元过度兴奋可能是由于电压依赖性钠通道表达增加所致。因此推测电压门控钠通道(VGSC或Nav)1.6亚型参与了兴奋性细胞动作电位的形成，并且可以直接影响神经元网络的兴奋性。我们近期的研究结果表明使用siRNA降低APP/PS1转基因小鼠脑内海马Nav1.6的表达后，APP/PS1转基因小鼠海马区域的Aβ斑块沉积减少，突触损伤减轻，长时程增强(LTP)损伤也减轻并且APP/PS1小鼠的学习和记忆障碍得到改善。其机制可能是，干扰Nav1.6的表达可以降低依赖Aβ的BACE1的转录水平。在Aβ寡聚体存在的情况下，下调Nav1.6可以通过抑制反向钠钙交换来抑制细胞内钙超载，从而可以增加非活性NFAT1的水平并且减少BACE1的转录。因此我们得出结论，APP/PS1转基因小鼠海马中Nav1.6的下调可以降低神经元的兴奋性并且改善APP/PS1转基因小鼠的学习和记忆障碍。Nav1.6可能为治疗阿尔茨海默氏病提供新策略。