Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Int J Mol Sci. 2023 Sep 5;24(18):13676. doi: 10.3390/ijms241813676.
Tau proteins within the adult central nervous system (CNS) are found to be abnormally aggregated into heterogeneous filaments in neurodegenerative diseases, termed tauopathies. These tau inclusions are pathological hallmarks of Alzheimer's disease (AD), Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). The neuropathological hallmarks of these diseases burden several cell types within the CNS, and have also been shown to be abundantly phosphorylated. The mechanism(s) by which tau aggregates in the CNS is not fully known, but it is hypothesized that hyperphosphorylated tau may precede and further promote filament formation, leading to the production of these pathological inclusions. In the studies herein, we generated and thoroughly characterized two novel conformation-dependent tau monoclonal antibodies that bind to residues Pro218-Glu222, but are sensitive to denaturing conditions and highly modulated by adjacent downstream phosphorylation sites. These epitopes are present in the neuropathological hallmarks of several tauopathies, including AD, PiD, CBD, and PSP. These novel antibodies will further enable investigation of tau-dependent pathological inclusion formation and enhance our understanding of the phosphorylation signatures within tauopathies with the possibility of new biomarker developments.
在神经退行性疾病中，成年中枢神经系统（CNS）中的 Tau 蛋白被发现异常聚集到异质纤维中，称为 Tau 病。这些 Tau 包含物是阿尔茨海默病（AD）、匹克氏病（PiD）、皮质基底节变性（CBD）和进行性核上性麻痹（PSP）的病理学特征。这些疾病的神经病理学特征在 CNS 中的几种细胞类型中存在，并且已经被证明大量磷酸化。 Tau 在 CNS 中聚集的机制尚不完全清楚，但据推测，过度磷酸化的 Tau 可能先于并进一步促进纤维形成，导致这些病理性包含物的产生。在本研究中，我们生成并彻底表征了两种新型构象依赖性 Tau 单克隆抗体，它们与残基 Pro218-Glu222 结合，但对变性条件敏感，并受相邻下游磷酸化位点高度调节。这些表位存在于几种 Tau 病的神经病理学特征中，包括 AD、PiD、CBD 和 PSP。这些新型抗体将进一步促进 Tau 依赖性病理性包含物形成的研究，并增强我们对 Tau 病中磷酸化特征的理解，有可能开发新的生物标志物。
