Table_1_Genetic Background Influences the Propagation of Tau Pathology in Transgenic Rodent Models of Tauopathy.DOCX

Alzheimer’s disease (AD), the most common tauopathy, is an age-dependent, progressive neurodegenerative disease. Epidemiological studies implicate the role of genetic background in the onset and progression of AD. Despite mutations in familial AD, several risk factors have been implicated in sporadic AD, of which the onset is unknown. In AD, there is a sequential and hierarchical spread of tau pathology to other brain areas. Studies have strived to understand the factors that influence this characteristic spread. Using transgenic rat models with different genetic backgrounds, we reported that the genetic background may influence the manifestation of neurofibrillary pathology. In this study we investigated whether genetic background has an influence in the spread of tau pathology, using hippocampal inoculations of insoluble tau from AD brains in rodent models of tauopathy with either a spontaneously hypertensive (SHR72) or Wistar-Kyoto (WKY72) genetic background. We observed that insoluble tau from human AD induced AT8-positive neurofibrillary structures in the hippocampus of both lines. However, there was no significant difference in the amount of neurofibrillary structures, but the extent of spread was prominent in the W72 line. On the other hand, we observed significantly higher levels of AT8-positive structures in the parietal and frontal cortical areas in W72 when compared to SHR72. Interestingly, we also observed that the microglia in these brain areas in W72 were predominantly phagocytic in morphology (62.4% in parietal and 47.3% in frontal), while in SHR72 the microglia were either reactive or ramified (67.2% in parietal and 84.7% in frontal). The microglia in the hippocampus and occipital cortex in both lines were reactive or ramified structures. Factors such as gender or age are not responsible for the differences observed in these animals. Put together, our results, for the first time, show that the immune response modulating genetic variability is one of the factors that influences the propagation of tau neurofibrillary pathology.

阿尔茨海默病（AD），最常见的一种tau蛋白病，是一种与年龄相关的进行性神经退行性疾病。流行病学研究表明，遗传背景在AD的发病和进展中扮演着重要角色。尽管家族性AD中存在突变，但多种风险因素已被确认为散发性AD的诱因，其发病原因尚不明确。在AD中，tau病理学呈现一种连续且分层的传播至其他脑区的特征。研究致力于探究影响这种特定传播特性的因素。利用具有不同遗传背景的转基因大鼠模型，我们报道了遗传背景可能影响神经纤维病理学的表现。在本研究中，我们探讨了遗传背景是否会影响tau病理学的传播，通过在具有自发高血压（SHR72）或Wistar-Kyoto（WKY72）遗传背景的tau蛋白病鼠模型中接种来自AD脑部的不可溶性tau蛋白进行海马体接种。我们观察到来自人类AD的不可溶性tau蛋白在两个品系的海马体中均诱导了AT8阳性的神经纤维结构。然而，神经纤维结构数量上并未观察到显著差异，但在W72品系中传播范围更为显著。另一方面，与SHR72相比，W72品系的大脑顶叶和额叶皮层区域的AT8阳性结构水平显著升高。有趣的是，我们还观察到W72中这些脑区的微胶质细胞形态以吞噬为主（顶叶62.4%，额叶47.3%），而在SHR72中，微胶质细胞则表现为反应性或分支状（顶叶67.2%，额叶84.7%）。两个品系的海马体和枕叶皮层的微胶质细胞均为反应性或分支状结构。性别或年龄等因素并非导致这些动物差异的原因。综合来看，我们的研究结果首次表明，免疫反应调节的遗传变异性是影响tau神经纤维病理学传播的因素之一。