To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer\'s disease (AD), age-matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons.
Expression of specific HCN channels is elevated in post mortem AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization-induced membrane voltage \"sag\" and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents.
Our findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network-wide structural and functional synaptic deficits.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are functionally linked to the development of tauopathy. Expression of specific HCN channels is elevated in the hippocampus in Alzheimer\'s disease and the Tau35 mouse model of tauopathy. Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization-induced membrane voltage \"sag\" demonstrating a detrimental effect of tau abnormalities on HCN channel function. Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice.
方法:为了研究tau和HCN通道之间的联系,我们做了组织学检查,生物化学,超微结构,和阿尔茨海默病(AD)海马组织的功能分析,年龄匹配的对照,Tau35老鼠,和/或Tau35原代海马神经元。
结果:特定HCN通道在死后AD海马中的表达升高。Tau35小鼠出现进行性异常,包括磷酸化tau增加,HCN通道表达增强,树突状分支减少,突触密度降低,和囊泡聚类缺陷。Tau35原代神经元显示HCN通道表达增加,增强了超极化诱导的膜电压“凹陷”,并改变了自发兴奋性突触后电流的频率和动力学。
结论:我们的发现与tau蛋白病变的病理变化影响HCN通道以驱动网络范围的结构和功能突触缺陷的模型一致。
结论:超极化激活的环核苷酸门控(HCN)通道在功能上与tau蛋白病的发展有关。在阿尔茨海默病和Tau病的Tau35小鼠模型中,海马中特定HCN通道的表达升高。Tau35小鼠中HCN通道表达的增加伴随着超极化诱导的膜电压“凹陷”,表明tau异常对HCN通道功能的不利影响。Tau35表达改变突触组织,导致Tau35小鼠的囊泡聚集表型松动。