With evidence supporting the prion-like spreading of extracellular tau as a mechanism for the initiation and progression of Alzheimer’s disease (AD), immunotherapy has emerged as a potential disease-modifying strategy to target tau. Many studies have proven effective to clear pathological tau species in animal models of AD, and several clinical trials using conventional immunotherapy with anti-tau native antibodies are currently active. We have previously generated a vectorized scFv derived from the conformation-dependent anti-tau antibody MC1, scFvMC1, and demonstrated that its intracranial injection was able to prevent tau pathology in adult tau mice. Here, we show that, in a prevention paradigm and in two different tau transgenic models (JNPL3 and P301S), a one-time intramuscular injection of AAV1-scFvMC1 generated a long-lasting peripheral source of anti-tau scFvMC1 and significantly reduced insoluble and soluble tau species in the brain. Moreover, our data showed that scFvMC1 was internalized by the microglia, in the absence of overt inflammation. This study demonstrates the efficacy of intramuscular delivery of vectorized scFv to target tau, and suggests a new potential application to treat AD and the other tauopathies.

中文翻译：

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在两种不同的 tau 转基因模型中，肌肉注射矢量化 scFvMC1 可减少病理性 tau。


有证据支持细胞外 tau 蛋白类似朊病毒的扩散是阿尔茨海默氏病 (AD) 发生和进展的机制，因此免疫疗法已成为针对 tau 蛋白的潜在疾病缓解策略。许多研究已证明可以有效清除 AD 动物模型中的病理性 tau 物种，并且目前正在进行一些使用抗 tau 天然抗体进行常规免疫治疗的临床试验。我们之前已经生成了一种源自构象依赖性抗 tau 抗体 MC1 的矢量化 scFv，scFvMC1，并证明其颅内注射能够预防成年 tau 小鼠的 tau 病理。在这里，我们表明，在预防范式和两种不同的 tau 转基因模型（JNPL3 和 P301S）中，一次性肌肉注射 AAV1-scFvMC1 产生了持久的外周抗 tau scFvMC1 来源，并显着减少了不溶性和大脑中可溶性 tau 蛋白。此外，我们的数据表明，在没有明显炎症的情况下，scFvMC1 被小胶质细胞内化。这项研究证明了肌肉注射矢量化 scFv 靶向 tau 的功效，并提出了治疗 AD 和其他 tau 病的新潜在应用。