We have derived single-chain variable fragments (scFv) from tau antibody hybridomas and previously shown their promise as imaging diagnostic agents. Here, we examined the therapeutic potential of anti-tau scFv in transgenic Drosophila models that express in neurons wild-type (WT) human tau (htau) or the human tauopathy mutation R406W. scFv expressing flies were crossed with the tauopathy flies and analyzed. Overall, the survival curves differed significantly (p < .0001). Control flies not expressing htau survived the longest, whereas R406W expressing flies had the shortest lifespan, which was greatly prolonged by co-expressing the anti-tau scFv (p < .0001). Likewise, htau WT expressing flies had a moderately short lifespan, which was prolonged by co-expressing the anti-tau scFv (p < .01). In addition, the htau expression impaired wing expansion after eclosion (p < .0001), and caused progressive abdomen expansion (p < .0001). These features were more severe in htau R406W flies than in htau WT flies. Importantly, both phenotypes were prevented by co-expression of the anti-tau scFv (p < .01-0.0001). Lastly, brain analyses revealed scFv-mediated tau clearance (p < .05-0.01), and its prevention of tau-mediated neurotoxicity (p < .05-0.001). In summary, these findings support the therapeutic potential of an anti-tau scFv, including as gene therapies, and the use of Drosophila models for such screening.

中文翻译：

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神经元表达的抗tau scFv可防止果蝇模型中tauopathy诱导的表型。

我们已经从tau抗体杂交瘤中获得了单链可变片段（scFv），并且先前显示了它们作为成像诊断剂的前景。在这里，我们检查了抗tau scFv在以神经元野生型（WT）人tau（htau）或人tauopathy突变R406W表示的神经元中表达的果蝇模型中的治疗潜力。将表达scFv的果蝇与tauopathy果蝇杂交并进行分析。总体而言，生存曲线差异显着（p <.0001）。不表达htau的对照果蝇存活时间最长，而表达R406W的果蝇寿命最短，通过共表达抗tau scFv可以大大延长其寿命（p <.0001）。同样，表达htau WT的果蝇的寿命适度较短，通过共表达抗tau scFv可以延长其寿命（p <.01）。此外，htau表情削弱了在羽化后的机翼扩张（p <.0001），并导致进行性腹部扩张（p <.0001）。这些特征在htau R406W苍蝇中比在htau WT苍蝇中更为严重。重要的是，两种表型均通过抗tau scFv的共表达而被阻止（p <.01-0.0001）。最后，大脑分析显示scFv介导的tau清除率（p <.05-0.01），以及其对tau介导的神经毒性的预防（p <.05-0.001）。总之，这些发现支持了抗tau scFv的治疗潜力，包括作为基因疗法，以及使用果蝇模型进行此类筛选。两种表型均通过抗tau scFv的共表达而被阻止（p <.01-0.0001）。最后，大脑分析显示scFv介导的tau清除率（p <.05-0.01），以及其对tau介导的神经毒性的预防（p <.05-0.001）。总之，这些发现支持了抗tau scFv的治疗潜力，包括作为基因疗法，以及使用果蝇模型进行此类筛选。两种表型均通过抗tau scFv的共表达而被阻止（p <.01-0.0001）。最后，大脑分析显示scFv介导的tau清除率（p <.05-0.01），以及其对tau介导的神经毒性的预防（p <.05-0.001）。总之，这些发现支持了抗tau scFv的治疗潜力，包括作为基因疗法，以及使用果蝇模型进行此类筛选。