Tau Phosphorylation in a Mouse Model of Temporal Lobe Epilepsy
Tau Phosphorylation in a Mouse Model of Temporal Lobe Epilepsy
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DOI：
10.3389/fnagi.2019.00308
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发表时间：
2019-11-12
影响因子：
4.8
通讯作者：
Engel, Tobias
中科院分区：
文献类型：
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作者：
Alves, Marianna;Kenny, Aidan;Engel, Tobias
微管相关蛋白tau的过度磷酸化及其聚集形成的神经纤维缠结(NFT)是神经退行性疾病(Tauopathies)的病理特征。Tau是一种神经元蛋白，参与轴突微管结构的稳定，tau的异常磷酸化与多种神经毒性作用有关。在颞叶癫痫(TLE)患者的大脑皮质中发现tau的病理和聚集体，引起了人们对tau过度磷酸化的兴趣，认为tau过度磷酸化是导致过度兴奋和认知功能下降的潜在机制。以前使用癫痫持续状态动物模型和TLE患者组织的研究表明，急性癫痫发作后和癫痫期间大脑中tau磷酸化增加，tau磷酸化与患者的认知障碍相关。在tau缺乏和tau过度表达的小鼠身上的研究表明，tau在癫痫的发生过程中起到了因果作用，这表明tau在癫痫的发生中发挥了作用。以前分析癫痫发作对tau过度磷酸化的影响的研究主要使用急性癫痫的动物模型。然而，这些模型并不能复制慢性癫痫的所有方面。在这项研究中，我们利用杏仁核海人酸(KA)诱导的癫痫持续状态小鼠模型，研究了急性癫痫发作(癫痫持续状态)和慢性癫痫对tau表达和磷酸化的影响。癫痫持续状态导致海马区，特别是齿状回的总tau水平立即升高，并导致AT8表位(Ser202，Thr205)的磷酸化，磷酸化的tau主要定位于齿状回苔藓纤维。在癫痫发作期间，在海马区CA3和CA1区的总tau水平较低的AT8表位，再次检测到tau的异常磷酸化。慢性癫痫小鼠还导致AT8磷酸化tau强烈定位于小胶质细胞，表明与癫痫持续状态相比，慢性癫痫期间tau过度磷酸化的模式截然不同。我们的结果重申了先前在癫痫持续状态后观察到的tau磷酸化，但也详细阐述了癫痫小鼠中tau的变化，这更忠实地模拟了TLE。我们的结果证实癫痫发作影响tau的过度磷酸化，然而，提示tau的表位特异性磷酸化和根据疾病进展的细胞特异性定位的不同。
Hyperphosphorylation of the microtubule-associated protein tau and its resultant aggregation into neurofibrillary tangles (NFT) is a pathological characteristic of neurodegenerative disorders known as tauopathies. Tau is a neuronal protein involved in the stabilization of microtubule structures of the axon and the aberrant phosphorylation of tau is associated with several neurotoxic effects. The discovery of tau pathology and aggregates in the cortex of Temporal lobe epilepsy (TLE) patients has focused interest on hyperphosphorylation of tau as a potential mechanism contributing to increased states of hyperexcitability and cognitive decline. Previous studies using animal models of status epilepticus and tissue from patients with TLE have shown increased tau phosphorylation in the brain following acute seizures and during epilepsy, with tau phosphorylation correlating with cognitive deficits in patients. Suggesting a functional role of tau during epilepsy, studies in tau-deficient and tau-overexpressing mice have demonstrated a causal role of tau during seizure generation. Previous studies, analyzing the impact of seizures on tau hyperphosphorylation, have mainly used animal models of acute seizures. These models, however, do not replicate all aspects of chronic epilepsy. In this study, we investigated the effects of acute seizures (status epilepticus) and chronic epilepsy upon the expression and phosphorylation of tau using the intra-amygdala kainic acid (KA)-induced status epilepticus mouse model. Status epilepticus resulted in an immediate increase in total tau levels in the hippocampus, in particular, the dentate gyrus, and phosphorylation of the AT8 epitope (Ser202, Thr205), with phosphorylated tau mainly localizing to the mossy fibers of the dentate gyrus. During epilepsy, abnormal phosphorylation of tau was detected again at the AT8 epitope with lower total tau levels in the CA3 and CA1 subfields of the hippocampus. Chronic epilepsy in mice also resulted in a strong localization of AT8 phospho-tau to microglia, indicating a distinct pattern of tau hyperphosphorylation during chronic epilepsy compared to status epilepticus. Our results reaffirm previous observations of tau phosphorylation post-status epilepticus, but also elaborate on tau alterations in epileptic mice which more faithfully mimic TLE. Our results confirm seizures affect tau hyperphosphorylation, however, suggest epitope-specific phosphorylation of tau and differences in cell-specific localization according to disease progression.