Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC, USA.
Mol Neurodegener. 2024 Nov 29;19(1):92. doi: 10.1186/s13024-024-00781-1.
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.
Tau 病是一组与年龄相关的神经退行性疾病，其特征是大脑中病理性过度磷酸化的 Tau 蛋白积累，导致类似朊病毒的聚集和传播。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 Pick 病（PiD）。目前，缺乏可靠的诊断生物标志物，这些标志物能够直接反映错误折叠的 Tau 聚集物在周围组织和体液中的传播和扩散能力。
我们利用种子扩增测定（SAA）结合超灵敏实时液流诱导转换（RT-QuIC），评估了经神经病理学证实的 Tau 病（包括 AD、PSP、CBD 和 PiD）尸检皮肤中病理性 Tau 的类似朊病毒的种子活性，与正常对照组进行比较。
我们发现，皮肤 Tau-SAA 在检测 Tau 病方面具有较高的敏感性（75-80%）和特异性（95-100%），这取决于所使用的 Tau 底物。此外，还观察到活的 AD 和 PSP 患者活检皮肤样本中 Tau 种子活性增加。皮肤 Tau-SAA 终产物分析证实，增加的种子活性伴随着不同理化性质的 Tau 聚集物的形成，这些聚集物与使用的两种不同 Tau 底物有关。
总体而言，我们的研究提供了皮肤 Tau-SAA 可区分 Tau 病与正常对照的概念验证，表明皮肤中错误折叠 Tau 的种子活性可作为 Tau 病的诊断生物标志物。
