Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles
Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles
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DOI：
10.1074/jbc.m110.209296
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发表时间：
2011-04-29
影响因子：
4.8
通讯作者：
Lee, Virginia M. -Y.
中科院分区：
文献类型：
--
作者：
Guo, Jing L.;Lee, Virginia M. -Y.
阿尔茨海默氏病和相关的tauopathies中的神经原纤维缠结（NFT）由不溶性的高磷酸化tau蛋白组成，但是将高度溶解的Tau转化为不溶性不溶的NFT的机制仍然难以捉摸。在这里，我们证明了将微量折叠的预先形成的tau纤维（tau pffs）引入表达tau的细胞中，迅速将大量可溶性tau募集到类似于前所未有的效率的nfts中的丝状夹杂物中，表明“播种” - 播种过程”。 NFT形成的合理机制在体内。与引起疾病的淀粉样蛋白蛋白类似prion样的可传递性的新兴概念一致，我们发现可能自发地摄取Tau PFF进入细胞，这可能是通过内吞作用介导的，这表明是tauopathy Brains中Tau病变传播的潜在机制。此外，PFF诱导的Tau聚集体对可溶性TAU进行了隔离，这会减弱表达Tau的细胞中的微管过度稳定，从而支持了具有NFTS的细胞中TAU功能丧失毒性的假设。总而言之，我们的研究建立了一个细胞系统，该细胞系统可靠地发展出真实的NFT样TAU聚集体，该骨料可提供对NFT发病机理的机械见解，并可以识别基于TAU的治疗剂的潜在工具。
Neurofibrillary tangles (NFTs) in Alzheimer disease and related tauopathies are composed of insoluble hyperphosphorylated Tau protein, but the mechanisms underlying the conversion of highly soluble Tau into insoluble NFTs remain elusive. Here, we demonstrate that introduction of minute quantities of misfolded preformed Tau fibrils (Tau pffs) into Tau-expressing cells rapidly recruit large amounts of soluble Tau into filamentous inclusions resembling NFTs with unprecedented efficiency, suggesting a "seeding"-recruitment process as a highly plausible mechanism underlying NFT formation in vivo. Consistent with the emerging concept of prion-like transmissibility of disease-causing amyloidogenic proteins, we found that spontaneous uptake of Tau pffs into cells is likely mediated by endocytosis, suggesting a potential mechanism for the propagation of Tau lesions in tauopathy brains. Furthermore, sequestration of soluble Tau by pff-induced Tau aggregates attenuates microtubule overstabilization in Tau-expressing cells, supporting the hypothesis of a Tau loss-of-function toxicity in cells harboring NFTs. In summary, our study establishes a cellular system that robustly develops authentic NFT-like Tau aggregates, which provides mechanistic insights into NFT pathogenesis and a potential tool for identifying Tau-based therapeutics.