Tau is a microtubule binding protein which plays an important role in physiological functions but it is also involved in the pathogenesis of Alzheimer's disease and related tauopathies. While insoluble and β-sheet containing tau neurofibrillary tangles have been the histopathological hallmark of these diseases, recent studies suggest that soluble tau oligomers, which are formed prior to fibrils, are the primary toxic species. Substantial efforts have been made to generate tau oligomers using purified recombinant protein strategies to study oligomer conformations as well as their toxicity. However, no specific toxic tau species has been identified to date, potentially due to the lack of cellular environment. Hence, there is a need for cell-based models for direct monitoring of tau oligomerization and aggregation. This review will summarize the recent advances in the cellular biosensor technology, with a focus on fluorescence resonance energy transfer, bimolecular fluorescence complementation, and split luciferase complementation approaches, to monitor formation of tau oligomers and aggregates in living cells. We will discuss the applications of the cellular biosensors in examining the heterogeneous tau conformational ensembles and factors affecting tau self-assembly, as well as detecting cell-to-cell propagation of tau pathology. We will also compare the advantages and limitations of each type of tau biosensors, and highlight their translational applications in biomarker development and therapeutic discovery.

中文翻译：

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研究 tau 寡聚化的细胞生物传感器技术的最新进展


Tau 是一种微管结合蛋白，在生理功能中发挥重要作用，但也参与阿尔茨海默病和相关 tau 病的发病机制。虽然不溶性和含有 β-折叠的 tau 神经原纤维缠结是这些疾病的组织病理学标志，但最近的研究表明，在原纤维之前形成的可溶性 tau 寡聚体是主要的有毒物质。人们已经做出了大量努力，利用纯化的重组蛋白策略来生成 tau 寡聚物，以研究寡聚物的构象及其毒性。然而，迄今为止，尚未发现特定的有毒 tau 蛋白种类，这可能是由于缺乏细胞环境。因此，需要基于细胞的模型来直接监测 tau 寡聚和聚集。本综述将总结细胞生物传感器技术的最新进展，重点关注荧光共振能量转移、双分子荧光互补和裂解荧光素酶互补方法，以监测活细胞中 tau 寡聚物和聚集体的形成。我们将讨论细胞生物传感器在检查异质 tau 构象整体和影响 tau 自组装的因素以及检测 tau 病理学的细胞间传播方面的应用。我们还将比较每种类型 tau 生物传感器的优点和局限性，并重点介绍它们在生物标志物开发和治疗发现中的转化应用。