Alzheimer’s disease(AD) is an age-associated neurodegenerative disease that results in deterioration of memory and cognitive function. As a currently untreatable disorder, AD has emerged as one of the defining biomedical challenges of our time. Thus, new approaches that can examine the cellular and molecular mechanisms underlying age-related AD pathology are sorely needed. One of the hallmarks of Alzheimer’s disease is the hyperphosphorylation of the tau protein. Caenorhabditis elegans have been previously used to study the genetic pathways impacted by tau proteotoxic stress; however, currently, available C. elegans tau models express the human protein solely in neurons, which are unresponsive to global RNA interference (RNAi). This limits powerful RNAi screening methods from being utilized effectively in these disease models. Our goal was to develop a C. elegans tau model that has pronounced tau-induced disease phenotypes in cells that can be modified by feeding RNAi methods. Towards this end, we generated a novel C. elegans transgenic line with codon-optimized human 0N4R V337M tau expressed in the body wall muscle under the myo-3 promoter. Immunoblotting experiments revealed that the expressed tau is phosphorylated on epitopes canonically associated with human AD pathology. The tau line has significantly reduced health metrics, including egg laying, growth rate, paralysis, thrashing frequency, crawling speed, and lifespan. These defects are suppressed by RNAi directed against the tau mRNA. Taken together, our results suggest that this alternative tau genetic model could be a useful tool for uncovering the mechanisms that influence the hyperphosphorylation and toxicity of human tau via RNAi screening and other approaches.

阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，会导致记忆和认知功能恶化。作为一种目前无法治疗的疾病，AD 已成为我们这个时代定义的生物医学挑战之一。因此，迫切需要能够检查与年龄相关的 AD 病理学的细胞和分子机制的新方法。阿尔茨海默病的特征之一是 tau 蛋白的过度磷酸化。秀丽隐杆线虫以前曾被用来研究受 tau 蛋白毒性应激影响的遗传途径；然而，目前可用的线虫tau 模型仅在神经元中表达人类蛋白，而神经元对整体 RNA 干扰 (RNAi) 没有反应。这限制了强大的 RNAi 筛选方法在这些疾病模型中的有效利用。我们的目标是开发一种秀丽隐杆线虫 tau 模型，该模型在细胞中具有明显的 tau 诱导疾病表型，并且可以通过喂食 RNAi 方法进行修改。为此，我们生成了一种新的秀丽隐杆线虫转基因系，其密码子优化的人 0N4R V337M tau 在myo-3启动子下在体壁肌肉中表达。免疫印迹实验表明，表达的 tau 蛋白在与人类 AD 病理学典型相关的表位上被磷酸化。tau 细胞系显着降低了健康指标，包括产蛋量、生长速度、麻痹、抖动频率、爬行速度和寿命。这些缺陷可通过针对 tau mRNA 的 RNAi 来抑制。总而言之，我们的结果表明，这种替代 tau 基因模型可能是一个有用的工具，可以通过 RNAi 筛选和其他方法揭示影响人类 tau 过度磷酸化和毒性的机制。