Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically hyperphosphorylated tau protein in the brain, leading to prion-like aggregation and propagation. They include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking. We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls. We found that the skin tau-SAA demonstrated a significantly higher sensitivity (75–80%) and specificity (95–100%) for detecting tauopathy, depending on the tau substrates used. Moreover, the increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used. Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.

中文翻译：

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皮肤错误折叠的 tau 蛋白的接种活性作为 tau 蛋白病的生物标志物


tau 蛋白病是一组与年龄相关的神经退行性疾病，其特征是病理性过度磷酸化的 tau 蛋白在大脑中积累，导致朊病毒样聚集和繁殖。它们包括阿尔茨海默病 （AD）、进行性核上性麻痹 （PSP）、皮质基底节变性 （CBD） 和皮克病 （PiD）。目前，缺乏可靠的诊断生物标志物，直接反映错误折叠的 tau 聚集体在外周组织和体液中的传播和扩散能力。我们利用种子扩增试验 （SAA） 采用超灵敏实时地震诱导转化 （RT-QuIC） 来评估病理性 tau 在患有神经病理学证实的 tau 病（包括 AD 、 PSP 、 CBD 和 PiD）的尸体皮肤中的朊病毒样接种活性，与正常对照相比。我们发现，皮肤 tau-SAA 在检测 tau 蛋白病方面表现出显着更高的敏感性 （75-80%） 和特异性 （95-100%），具体取决于所使用的 tau 底物。此外，在接受检查的活体 AD 和 PSP 患者的活检皮肤样本中也观察到 tau 接种活性增加。对皮肤 tau SAA 最终产物的分析证实，接种活性的增加伴随着与使用的两种不同 tau 底物相关的具有不同物理化学性质的 tau 聚集体的形成。总体而言，我们的研究提供了概念验证，即皮肤 tau-SAA 可以将 tau 蛋白病与正常对照区分开来，这表明错误折叠的 tau 蛋白在皮肤中的播种活性可以作为 tau 蛋白病的诊断生物标志物。