Tau protein abnormally aggregates in tauopathies, a diverse group of neurologic diseases that includes Alzheimer’s disease (AD). In early stages of disease, tau becomes hyperphosphorylated and mislocalized, which can contribute to its aggregation and toxicity. We demonstrate that tau phosphorylation at Ser208 (pSer208) promotes microtubule dysfunction and tau aggregation in cultured cells. Comparative assessment of the epitopes recognized by antibodies AT8, CP13, and 7F2 demonstrates that CP13 and 7F2 are specific for tau phosphorylation at Ser202 and Thr205, respectively, independently of the phosphorylation state of adjacent phosphorylation sites. Supporting the involvement of pSer208 in tau pathology, a novel monoclonal antibody 3G12 specific for tau phosphorylation at Ser208 revealed strong reactivity of tau inclusions in the brains of PS19 and rTg4510 transgenic mouse models of tauopathy. 3G12 also labelled neurofibrillary tangles in brains of patients with AD but revealed differential staining compared to CP13 and 7F2 for other types of tau pathologies such as in neuropil threads and neuritic plaques in AD, tufted astrocytes in progressive supranuclear palsy and astrocytic plaques in corticobasal degeneration. These results support the hypothesis that tau phosphorylation at Ser208 strongly contributes to unique types of tau aggregation and may be a reliable marker for the presence of mature neurofibrillary tangles.

中文翻译：

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Tau Ser208磷酸化促进聚集，并揭示阿尔茨海默氏病和其他陶氏病的神经病理学多样性。

Tau蛋白在Tauopathies中异常聚集，后者是包括Alzheimer病（AD）在内的多种神经系统疾病。在疾病的早期，tau过度磷酸化和定位错误，这可能有助于其聚集和毒性。我们证明在Ser208（pSer208）的tau磷酸化促进培养细胞中的微管功能障碍和tau聚集。对抗体AT8，CP13和7F2识别的表位的比较评估表明，CP13和7F2分别对Ser202和Thr205的tau磷酸化具有特异性，而与相邻磷酸化位点的磷酸化状态无关。支持pSer208参与tau病理学研究，特异性针对Ser208上tau磷酸化的新型单克隆抗体3G12揭示了tau蛋白PS19和rTg4510转基因小鼠模型脑中tau内含物的强反应性。3G12还标记了AD患者大脑中的神经原纤维缠结，但与其他类型的tau病理相比，CP13和7F2表现出差异性染色，例如在AD中的神经纤维和神经斑，簇状星形胶质细胞在渐进性核上性麻痹和星形胶质斑在皮质基底变性中。这些结果支持这样的假设，即Ser208处的tau磷酸化强烈促进tau聚集的独特类型，并且可能是存在成熟神经原纤维缠结的可靠标记。3G12还标记了AD患者大脑中的神经原纤维缠结，但与其他类型的tau病理相比，CP13和7F2表现出差异性染色，例如在AD中的神经纤维和神经斑，簇状星形胶质细胞在渐进性核上性麻痹和星形胶质斑在皮质基底变性中。这些结果支持这样的假设，即Ser208处的tau磷酸化强烈促进tau聚集的独特类型，并且可能是存在成熟神经原纤维缠结的可靠标记。3G12还标记了AD患者大脑中的神经原纤维缠结，但与其他类型的tau病理相比，CP13和7F2表现出差异性染色，例如在AD中的神经纤维和神经斑，簇状星形胶质细胞在渐进性核上性麻痹和星形胶质斑在皮质基底变性中。这些结果支持这样的假设，即Ser208处的tau磷酸化强烈促进tau聚集的独特类型，并且可能是存在成熟神经原纤维缠结的可靠标记。