Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations.
Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations.
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DOI：
10.1155/2013/260787
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发表时间：
2013
影响因子：
--
通讯作者：
Sierks M
中科院分区：
文献类型：
--
作者：
Tian H;Davidowitz E;Lopez P;Emadi S;Moe J;Sierks M
在阿尔茨海默病（AD）中，tau聚集成原纤维和高级神经元缠结，这是AD的关键组织病理学特征。然而，可溶性寡聚tau种类可能在AD进展中起更关键的作用，因为这些tau种类与神经元损失和认知功能障碍更好地相关。最近的研究表明，细胞外寡聚tau可以抑制记忆形成和突触功能，并将病理传递给邻近的神经元。然而，涉及毒性的寡聚tau的具体形式仍然未知。在这里，我们使用了重组人tau蛋白的两种剪接变体，并产生了每种亚型的单体、二聚体和三聚体部分。每个馏分的组成进行了验证色谱，也通过原子力显微镜。评估了各组分对人神经母细胞瘤细胞和胆碱能样神经元的毒性。两种剪接变体的三聚体，而不是单体或二聚体，tau寡聚体在低纳摩尔浓度下具有神经毒性。具有疾病特异性修饰和形态的tau寡聚体种类的进一步表征对于鉴定用于开发AD和相关tau蛋白病的生物标志物和治疗开发的最佳靶标是必要的。
In Alzheimer's disease (AD), tau aggregates into fibrils and higher order neurofibrillary tangles, a key histopathological feature of AD. However, soluble oligomeric tau species may play a more critical role in AD progression since these tau species correlate better with neuronal loss and cognitive dysfunction. Recent studies show that extracellular oligomeric tau can inhibit memory formation and synaptic function and also transmit pathology to neighboring neurons. However, the specific forms of oligomeric tau involved in toxicity are still unknown. Here, we used two splice variants of recombinant human tau and generated monomeric, dimeric, and trimeric fractions of each isoform. The composition of each fraction was verified chromatographically and also by atomic force microscopy. The toxicity of each fraction toward both human neuroblastoma cells and cholinergic-like neurons was assessed. Trimeric, but not monomeric or dimeric, tau oligomers of both splice variants were neurotoxic at low nanomolar concentrations. Further characterization of tau oligomer species with disease-specific modifications and morphologies is necessary to identify the best targets for the development of biomarker and therapeutic development for AD and related tauopathies.