Huang Melissa, McEwan William A
UK Dementia Research Institute at the University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom.
J Biol Chem. 2025 Mar;301(3):108245. doi: 10.1016/j.jbc.2025.108245. Epub 2025 Jan 27.
The assembly of tau into filaments defines tauopathies, a group of neurodegenerative diseases including Alzheimer's disease (AD), Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). The seeded aggregation of tau has been modeled in cell culture using pro-aggregate modifications such as truncation of N- and C-termini and point mutations within the microtubule-binding repeat domain. This limits the applicability of research findings to sporadic disease, where aggregates contain wild-type, full-length tau. We describe a sensitive and specific biosensor assays for brain-derived tau species utilizing wild-type 0N3R and 0N4R tau expressed in HEK293 cells. We further generate a cell line that propagates AD-templated insoluble tau which is hyperphosphorylated at disease-relevant sites and retains a seeding profile similar to AD. We propose these systems as an advance over existing cell-based seeding assays, as they display specificity to the conformation and isoform composition of sporadic human disease.
tau蛋白组装成细丝定义了tau蛋白病，这是一组神经退行性疾病，包括阿尔茨海默病（AD）、皮克病（PiD）、皮质基底节变性（CBD）和进行性核上性麻痹（PSP）。tau蛋白的种子样聚集已在细胞培养中通过促聚集修饰进行模拟，如N端和C端的截断以及微管结合重复结构域内的点突变。这限制了研究结果对散发性疾病的适用性，在散发性疾病中，聚集体包含野生型全长tau蛋白。我们描述了一种利用在HEK293细胞中表达的野生型0N3R和0N4R tau蛋白对脑源性tau蛋白种类进行灵敏且特异的生物传感器检测方法。我们进一步构建了一个细胞系，该细胞系能传播以AD为模板的不溶性tau蛋白，这种tau蛋白在疾病相关位点高度磷酸化，并保留与AD相似的种子样特征。我们认为这些系统比现有的基于细胞的种子样检测方法更先进，因为它们对散发性人类疾病的构象和异构体组成具有特异性。
