Amyloid β-Induced Upregulation of Nav1.6 Underlies Neuronal Hyperactivity in Tg2576 Alzheimer's Disease Mouse Model
Amyloid β-Induced Upregulation of Nav1.6 Underlies Neuronal Hyperactivity in Tg2576 Alzheimer's Disease Mouse Model
复制标题
DOI：
10.1038/s41598-019-50018-1
复制
发表时间：
2019-09-19
影响因子：
4.6
通讯作者：
Pannaccione, Anna
中科院分区：
文献类型：
--
作者：
Ciccone, Roselia;Franco, Cristina;Pannaccione, Anna
神经元网络的过度兴奋和改变有助于阿尔茨海默病（AD）的认知障碍。电压门控钠通道（Na-V）是调节神经元兴奋性的关键，与AD相关的海马活动过度和自发性非惊厥性癫痫发作的发生率较高有关。在这里，我们通过使用暴露于淀粉样蛋白β（1-42）（A β（1-42））寡聚体和Tg 2576小鼠胚胎的原代海马神经元显示，Na（V）1.6亚型的选择性上调有助于膜去极化和尖峰频率的增加，从而导致神经元过度兴奋。有趣的是，我们还发现Na（V）1.6过表达是导致在3个月大的Tg 2576小鼠海马切片中观察到的异常神经元活动的原因。这些发现确定Na（V）1.6通道是A β（1-42）寡聚体诱导的海马神经元过度兴奋的决定因素。因此，选择性阻断Na（V）1.6过表达和/或活动过度可能提供一种新的潜在治疗方法，以对抗AD早期海马过度兴奋和随后的认知缺陷。
Hyperexcitability and alterations in neuronal networks contribute to cognitive impairment in Alzheimer's Disease (AD). Voltage-gated sodium channels (Na-V), which are crucial for regulating neuronal excitability, have been implicated in AD-related hippocampal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we show by using primary hippocampal neurons exposed to amyloid-beta(1-42) (A beta(1-42)) oligomers and from Tg2576 mouse embryos, that the selective upregulation of Na(V)1.6 subtype contributes to membrane depolarization and to the increase of spike frequency, thereby resulting in neuronal hyperexcitability. Interestingly, we also found that Na(V)1.6 overexpression is responsible for the aberrant neuronal activity observed in hippocampal slices from 3-month-old Tg2576 mice. These findings identify the Na(V)1.6 channels as a determinant of the hippocampal neuronal hyperexcitability induced by A beta(1-42) oligomers. The selective blockade of Na(V)1.6 overexpression and/or hyperactivity might therefore offer a new potential therapeutic approach to counteract early hippocampal hyperexcitability and subsequent cognitive deficits in the early stages of AD.