Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.

IF 4.4 2区 医学 Q1 NEUROSCIENCES Journal of Neuroscience Pub Date : 2024-11-05 DOI:10.1523/JNEUROSCI.0877-24.2024
Elliot Jang, Kevt'her Hoxha, Damian Mozier, Abigail Insana, Ethan Farber, Lakshmi Changolkar, Bin Zhang, Tak-Ian Chio, Alex Crowe, Richard Chen, Marc Mercken, Edward B Lee, Kelvin C Luk, Kurt R Brunden, Virginia M-Y Lee, Hong Xu
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Abstract

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.Significance Statement The transmission of tau pathology plays key role in the pathoclinical progression of tauopathy. Studies have shown that tau antibody treatment can mitigate tau pathology in transgenic and spreading models of tauopathy. To explore the mechanisms involved in this procedure, we conducted immunotherapy studies on human tau seeds induced tau spreading models using a mouse tau-specific antibody (mTau8), which does not interact with human-tau seeds. Our findings in the study enhance our understanding of antibody-based therapies for tauopathies.

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在种子型 Tauopathy 模型中靶向内源性 Tau 可抑制 Tau 的扩散。
tau病理学的传递被认为是神经退行性疾病中tau病理学时空扩散的主要机制之一。在过去的十年中,研究表明,使用tau抗体靶向总tau或病理tau可以缓解tau病或阿尔茨海默病(AD)小鼠模型中tau病理学的发展,多种tau免疫疗法药物已进入临床试验阶段。Tau抗体被认为能抑制病理种子的内化和/或阻止种子内化后的伸长。为了进一步研究 tau 抗体抑制病理扩散的机制,我们在小鼠原始神经元和野生型小鼠(雌性)的免疫疗法研究中播下了 AD 患者来源的 tau 种子,以诱导 tau 病理的形成和扩散。值得注意的是,我们评估了小鼠tau特异性抗体(mTau8)在这些模型中的效果,该抗体与AD-tau种子没有相互作用。我们的结果表明,mTau8能穿过血脑屏障,其水平与其他抗体相似,并能在体外和体内有效减少AD-tau种子的tau病理变化。重要的是,我们的数据表明,mTau8能与小鼠内源性神经元内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治疗方法治疗tau病的可能机制提供了有价值的见解。 意义声明 tau病理学的传播在tau病的病理进展中起着关键作用。研究表明,在tau病的转基因模型和扩散模型中,tau抗体治疗可减轻tau病理变化。为了探索这一过程的相关机制,我们使用小鼠tau特异性抗体(mTau8)对人tau种子诱导的tau扩散模型进行了免疫治疗研究,该抗体与人tau种子没有相互作用。我们的研究结果加深了我们对基于抗体的tau病疗法的理解。
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来源期刊
Journal of Neuroscience
Journal of Neuroscience 医学-神经科学
CiteScore
9.30
自引率
3.80%
发文量
1164
审稿时长
12 months
期刊介绍: JNeurosci (ISSN 0270-6474) is an official journal of the Society for Neuroscience. It is published weekly by the Society, fifty weeks a year, one volume a year. JNeurosci publishes papers on a broad range of topics of general interest to those working on the nervous system. Authors now have an Open Choice option for their published articles
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