Alzheimer’s disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD). The prion hypothesis suggests that after an initial trigger event, misfolded forms of tau are released into the extracellular space, where they spread through different brain regions, enter cells, and seeding previously normal forms. Thus understanding mechanisms regulating the clearance of extracellular tau from the CNS is important. The discovery of a true lymphatic system in the dura and its potential role in mediating Aβ pathology prompted us to investigate its role in regulating extracellular tau clearance. To study clearance of extracellular tau from the brain, we conjugated monomeric human tau with a near-infrared dye cypate, and injected this labeled tau in the parenchyma of both wild-type and K14-VEGFR3-Ig transgenic mice, which lack a functional CNS lymphatic system. Following injection we performed longitudinal imaging using fluorescence molecular tomography (FMT) and quantified fluorescence to calculate clearance of tau from the brain. To complement this, we also measured tau clearance to the periphery by measuring plasma tau in both groups of mice. Our results show that a significantly higher amount of tau is retained in the brains of K14-VEGFR3-Ig vs. wild type mice at 48 and 72 h post-injection and its subsequent clearance to the periphery is delayed. We found that clearance of reference tracer human serum albumin (HSA) was also significantly delayed in the K14-VEGFR3-Ig mice. The dural lymphatic system appears to play an important role in clearance of extracellular tau, since tau clearance is impaired in the absence of functional lymphatics. Based on our baseline characterization of extracellular tau clearance, future studies are warranted to look at the interaction between tau pathology and efficiency of lymphatic function.

中文翻译：

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硬脑膜淋巴管调节中枢神经系统细胞外 tau 蛋白的清除

阿尔茨海默氏病有两个主要的神经病理学特征：β-淀粉样蛋白 (Aβ) 蛋白的细胞外斑块和 tau 蛋白的细胞内聚集物。尽管 tau 通常是结合微管的可溶性单体，但在疾病中，它会在细胞体内形成不溶性、过度磷酸化的聚集体。除了在 AD 中发挥作用外，tau 蛋白还与其他几种神经退行性疾病（统称为 tau蛋白病）有关，例如进行性核上性麻痹 (PSP)、皮质基底节变性 (CBD)、某些形式的额颞叶痴呆和嗜银颗粒病 (AGD)。朊病毒假说表明，在最初的触发事件后，错误折叠形式的 tau 蛋白被释放到细胞外空间，在那里它们扩散到不同的大脑区域，进入细胞，并播种以前的正常形式。因此，了解中枢神经系统清除细胞外 tau 蛋白的调节机制非常重要。硬脑膜中真正的淋巴系统的发现及其在介导 Aβ 病理学中的潜在作用促使我们研究其在调节细胞外 tau 清除中的作用。为了研究细胞外 tau 从大脑中的清除，我们将单体人 tau 与近红外染料 cypate 结合，并将这种标记的 tau 注射到缺乏功能性 CNS 的野生型和 K14-VEGFR3-Ig 转基因小鼠的实质中淋巴系统。注射后，我们使用荧光分子断层扫描 (FMT) 进行纵向成像，并定量荧光以计算 tau 从大脑中的清除率。为了补充这一点，我们还通过测量两组小鼠的血浆 tau 来测量 tau 到外周的清除率。我们的结果表明，与野生型小鼠相比，注射后 48 小时和 72 小时，K14-VEGFR3-Ig 的大脑中保留了明显更高量的 tau，并且随后其到外周的清除被延迟。我们发现 K14-VEGFR3-Ig 小鼠中参考示踪剂人血清白蛋白 (HSA) 的清除也显着延迟。硬脑膜淋巴系统似乎在细胞外 tau 蛋白的清除中发挥重要作用，因为在缺乏功能性淋巴管的情况下 tau 蛋白的清除会受到损害。根据我们对细胞外 tau 清除的基线特征，未来的研究有必要研究 tau 病理学与淋巴功能效率之间的相互作用。