Antisense Reduction of Tau in Adult Mice Protects against Seizures
Antisense Reduction of Tau in Adult Mice Protects against Seizures
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DOI：
10.1523/jneurosci.2107-13.2013
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发表时间：
2013-07-31
影响因子：
5.3
通讯作者：
Miller, Timothy M.
中科院分区：
文献类型：
--
作者：
DeVos, Sarah L.;Goncharoff, Dustin K.;Miller, Timothy M.
Tau是一种微管相关蛋白，在神经元缠结形成和神经元网络过度兴奋方面与阿尔茨海默病（AD）的发病机制有关。tau的遗传消融显著降低了AD小鼠系、诱导的癫痫发作模型和癫痫的遗传体内模型中的过度兴奋性。这些数据表明，tau蛋白是网络兴奋性的重要调节因子。然而，在遗传tau基因敲除线的发育补偿可能占癫痫发作的保护作用。为了测试tau蛋白减少疗法对成年动物中具有有害的过度兴奋性特征的疾病的功效，我们鉴定了选择性降低整个小鼠CNS-脑和脊髓组织、间质液和CSF-中的内源性tau蛋白表达的反义寡核苷酸，同时对基线运动或认知行为没有影响。在两种化学诱导的癫痫发作模型中，tau蛋白减少的小鼠癫痫发作的严重程度低于对照小鼠。总tau蛋白水平和癫痫发作严重程度高度相关，因此癫痫发作最严重的小鼠也具有最高的tau水平。我们的研究结果表明，内源性tau蛋白是不可或缺的调节神经元的过度兴奋在成年动物，并表明，反义寡核苷酸减少tau蛋白可能有利于那些与癫痫和其他疾病可能与tau蛋白介导的神经元过度兴奋。
Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) in regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation of tau substantially reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy. These data demonstrate that tau is an important regulator of network excitability. However, developmental compensation in the genetic tau knock-out line may account for the protective effect against seizures. To test the efficacy of a tau reducing therapy for disorders with a detrimental hyperexcitability profile in adult animals, we identified antisense oligonucleotides that selectively decrease endogenous tau expression throughout the entire mouse CNS-brain and spinal cord tissue, interstitial fluid, and CSF-while having no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced tau protein had less severe seizures than control mice. Total tau protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of tau. Our results demonstrate that endogenous tau is integral for regulating neuronal hyperexcitability in adult animals and suggest that an antisense oligonucleotide reduction of tau could benefit those with epilepsy and perhaps other disorders associated with tau-mediated neuronal hyperexcitability.