The transmission of tau pathology has been proposed as one of the major mechanisms for the spatiotemporal spreading of tau pathology in neurodegenerative diseases. Over the last decade, studies have demonstrated that targeting total or pathological tau using tau antibodies can mitigate the development of tau pathology in tauopathy or Alzheimer's disease (AD) mouse models, and multiple tau immunotherapy agents have progressed to clinical trials. Tau antibodies are believed to inhibit the internalization of pathologic seeds and/or block seed elongation after seed internalization. To further address the mechanism of tau antibody inhibition of pathological spread, we conducted immunotherapy studies in mouse primary neurons and wild-type mice (females) seeded with AD patient-derived tau to induce the formation and spreading of tau pathology. Notably, we evaluated the effect of a mouse tau-specific antibody (mTau8) which does not interact with AD–tau seeds in these models. Our results show that mTau8 crosses the blood–brain barrier at levels similar to other antibodies and effectively decreases AD–tau-seeded tau pathology in vitro and in vivo. Importantly, our data suggest that mTau8 binds to endogenous intraneuronal mouse tau, thereby inhibiting the elongation of internalized tau seeds. These findings provide valuable insights into the possible mechanism underlying antibody-based therapies for treating tauopathies.

tau 病理学的传播已被提议作为神经退行性疾病中 tau 病理学时空传播的主要机制之一。在过去的十年中，研究表明，使用 tau 抗体靶向总或病理 tau 可以减轻 tau 病或阿尔茨海默病 （AD） 小鼠模型中 tau 病理的发展，并且多种 tau 免疫治疗药物已进入临床试验。Tau 抗体被认为可抑制病理种子的内化和/或阻断种子内化后的种子伸长。为了进一步解决 tau 抗体抑制病理传播的机制，我们在小鼠原代神经元和野生型小鼠（雌性）中进行了免疫治疗研究，这些小鼠原代神经元和野生型小鼠（雌性）接种了 AD 患者来源的 tau 以诱导 tau 病理学的形成和扩散。值得注意的是，我们评估了在这些模型中不与 AD-tau 种子相互作用的小鼠 tau 特异性抗体 （mTau8） 的效果。我们的结果表明，mTau8 以与其他抗体相似的水平穿过血脑屏障，并在体外和体内有效降低 AD – tau 种子的 tau 病理学。重要的是，我们的数据表明 mTau8 与内源性神经元内小鼠 tau 结合，从而抑制内化 tau 种子的伸长。这些发现为基于抗体的疗法治疗 tau 蛋白病的可能机制提供了有价值的见解。