The Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
J Alzheimers Dis. 2013;37(3):569-77. doi: 10.3233/JAD-131106.
Neurofibrillary degeneration, driven by misfolded protein tau, spreads from the predisposed induction sites and advances in a topographically predictable sequence along connected brain areas. Several mouse model studies have demonstrated that some species of pathologically modified tau, namely insoluble fibrils and soluble oligomers, evoke propagation of the pathology. These results clearly show that the spreading potency of misfolded tau does not depend exclusively on its solubility and/or mutations. The candidate factor responsible for the progression of misfolded protein tau is its disease modified conformation. In this study, we address the question, whether insoluble tau complexes containing either 3R or 4R human misfolded truncated tau (AlzTau) command distinct infectivity and spreading potency. We found that insoluble tau isolated from transgenic rats (SHR24), expressing misfolded 3R AlzTau, was able to infect cortical neurons in the area of injection in SHR72 transgenic rats expressing 4R AlzTau. However this tau was not able to spread into other brain areas. In contrast, administration of insoluble tau isolated from SHR72 transgenic rats was not only able to infect cortical neurons but also induced extensive spreading of neurofibrillary tangles in the adjacent brain areas. These findings suggest the existence of various strains of disease modified tau, tauons displaying different infectivity and spreading potency. Furthermore, the presented rat tauopathy models could serve as a tool for identification and characterization of tauons isolated from Alzheimer's disease brains that would allow stratification of Alzheimer's disease patients.
神经原纤维缠结，由错误折叠的蛋白 tau 驱动，从易感性诱导部位开始扩散，并沿着连通的脑区以地形上可预测的顺序前进。几项小鼠模型研究表明，某些病理修饰的 tau 物种，即不溶性纤维和可溶性寡聚物，会引发病理学的传播。这些结果清楚地表明，错误折叠 tau 的扩散能力不仅取决于其溶解度和/或突变。导致错误折叠蛋白 tau 进展的候选因素是其疾病修饰构象。在这项研究中，我们探讨了这样一个问题，即是否含有 3R 或 4R 人错误折叠截断 tau（AlzTau）的不溶性 tau 复合物具有不同的感染力和扩散能力。我们发现，从表达错误折叠 3R AlzTau 的转基因大鼠（SHR24）中分离出的不溶性 tau 能够感染在表达 4R AlzTau 的 SHR72 转基因大鼠的注射区域中的皮质神经元。然而，这种 tau 不能扩散到其他脑区。相比之下，从 SHR72 转基因大鼠中分离出的不溶性 tau 不仅能够感染皮质神经元，而且还能诱导相邻脑区神经纤维缠结的广泛扩散。这些发现表明存在各种疾病修饰的 tau 株，tauons 显示出不同的感染力和扩散能力。此外，所提出的大鼠 tau 病模型可以作为从阿尔茨海默病大脑中分离出的 tauons 的鉴定和特征描述的工具，从而允许对阿尔茨海默病患者进行分层。
