Paterno Giavanna, Bell Brach M, Gorion Kimberly-Marie M, Quintin Stephan, Prokop Stefan, Giasson Benoit I
Department of Neuroscience, College of Medicine, University of Florida, BMS J483/CTRND, 1275 Center Drive, Gainesville, FL, 32610, USA.
Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
Sci Rep. 2025 Jun 5;15(1):19865. doi: 10.1038/s41598-025-04291-y.
Tauopathies are a group of clinically and neuropathologically diverse neurodegenerative disorders defined by the abnormal aggregation of tau protein. While tau is normally soluble with limited secondary structure, pathological tau is characterized by hyperphosphorylation and assembly into fibrils which accumulate in neurons and glial cells in the central nervous system. The contribution of aberrant tau phosphorylation towards the pathogenesis of distinct disease manifestations is highly debated, however, it is posited that a hyperphosphorylation state influences aggregate formation due to tau's inability to carry out its normal biological function(s). Due to the large number of potential phosphorylation sites on tau, determining the disease relevance of certain phosphorylation sites has remained challenging. Recent studies have demonstrated that tau phosphorylated at Thr217 can be detected in cerebrospinal fluid and plasma, is elevated in Alzheimer's disease (AD) compared to other neurodegenerative diseases and is highly associated with hallmark pathologies. To further explore the neuropathological profile of this tau phosphorylation site in AD and other primary tauopathies, we generated and characterized a novel phosphorylation-dependent monoclonal antibody, 1F10. It is demonstrated that 1F10 is selective for tau phosphorylation at Thr217, and that the epitope for 1F10 is augmented in cultured cells overexpressing glycogen synthase kinase-3β. Moreover, 1F10 labelled neurofibrillary tangle-like inclusions in a mouse model of tauopathy and hallmark tau neuropathological lesions characteristic of AD and primary tauopathies but with differentiating antigenic profiles.
tau蛋白病是一组临床和神经病理学表现多样的神经退行性疾病，其定义为tau蛋白的异常聚集。虽然tau蛋白通常是可溶的，二级结构有限，但病理性tau蛋白的特征是过度磷酸化并组装成原纤维，这些原纤维在中枢神经系统的神经元和神经胶质细胞中积累。异常的tau蛋白磷酸化对不同疾病表现发病机制的贡献存在高度争议，然而，据推测，由于tau蛋白无法执行其正常生物学功能，过度磷酸化状态会影响聚集体的形成。由于tau蛋白上存在大量潜在的磷酸化位点，确定某些磷酸化位点与疾病的相关性仍然具有挑战性。最近的研究表明，在脑脊液和血浆中可以检测到苏氨酸217位点磷酸化的tau蛋白，与其他神经退行性疾病相比，在阿尔茨海默病（AD）中其水平升高，并且与标志性病理特征高度相关。为了进一步探索该tau蛋白磷酸化位点在AD和其他原发性tau蛋白病中的神经病理学特征，我们制备并鉴定了一种新型的磷酸化依赖性单克隆抗体1F10。结果表明，1F10对苏氨酸217位点的tau蛋白磷酸化具有选择性，并且在过表达糖原合酶激酶-3β的培养细胞中，1F10的表位增强。此外，1F10在tau蛋白病小鼠模型中标记了神经原纤维缠结样包涵体以及AD和原发性tau蛋白病特有的标志性tau神经病理学病变，但具有不同的抗原谱。
