4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration
4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration
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DOI：
10.1007/s00401-019-02080-2
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发表时间：
2019-10-16
影响因子：
12.7
通讯作者：
Caughey, Byron
中科院分区：
文献类型：
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作者：
Saijo, Eri;Metrick, Michael A., II;Caughey, Byron
为了满足对更有意义的 tau 蛋白病生物标志物的需求，我们开发了一种超灵敏 tau 蛋白种子扩增测定 (4R RT-QuIC)，用于检测进行性核上性麻痹 (PSP)、皮质基底节变性 (CBD) 和其他 4R tau 蛋白病疾病的 4 次重复 (4R) tau 聚集体。该检测在 10(6)-10(9) 倍稀释的 4R tau 蛋白病脑组织中检测到种子，但对其他类型 tau 蛋白病（例如阿尔茨海默病病例）的大脑的反应要低几个数量级。合成 4R tau 原纤维的分析灵敏度为 50 fM 或 2 fg/样品。这种 tau RT-QuIC 测试的一个新颖之处是鉴定了三种与疾病相关的 4R tau 种子类别；这些类别是通过硫黄素 T 荧光振幅和 FTIR 光谱检测到的体外扩增 tau 原纤维的构象变化来揭示的。在所有经神经病理学证实的 PSP 和 CBD 病例的死后脑脊液 (CSF) 中均检测到 Tau 种子，但在对照中未检测到。来自活体受试者的脑脊液的播种活性较弱；然而，临床诊断为 PSP 和 CBD/皮质基底节综合征的病例的平均检测反应显着高于对照病例。总而言之，4R RT-QuIC 提供了一种实用的无细胞方法，用于检测作为生物标志物的病理性 4R tau 聚集体并对其进行分型。
To address the need for more meaningful biomarkers of tauopathies, we have developed an ultrasensitive tau seed amplification assay (4R RT-QuIC) for the 4-repeat (4R) tau aggregates of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other diseases with 4R tauopathy. The assay detected seeds in 10(6)-10(9)-fold dilutions of 4R tauopathy brain tissue but was orders of magnitude less responsive to brain with other types of tauopathy, such as from Alzheimer's disease cases. The analytical sensitivity for synthetic 4R tau fibrils was 50 fM or 2 fg/sample. A novel dimension of this tau RT-QuIC testing was the identification of three disease-associated classes of 4R tau seeds; these classes were revealed by conformational variations in the in vitro amplified tau fibrils as detected by thioflavin T fluorescence amplitudes and FTIR spectroscopy. Tau seeds were detected in postmortem cerebrospinal fluid (CSF) from all neuropathologically confirmed PSP and CBD cases but not in controls. CSF from living subjects had weaker seeding activities; however, mean assay responses for cases clinically diagnosed as PSP and CBD/corticobasal syndrome were significantly higher than those from control cases. Altogether, 4R RT-QuIC provides a practical cell-free method of detecting and subtyping pathologic 4R tau aggregates as biomarkers.