Dural lymphatics regulate clearance of extracellular tau from the CNS

作者：Tirth K. Patel, LeMoyne Habimana-Griffin, Xuefeng Gao, Baogang J. Xu, Samuel Achilefu, Kari K. Alitalo, Celia A. McKee, Patrick W. Sheehan, Erik S. Musiek, Chengjie Xiong, Dean W. Coble, David M. Holtzman · 发表于：Molecular Neurodegeneration · 年份：2019 · DOI：10.1186/s13024-019-0312-x · 被引用次数：221 · 研究领域：Cerebrospinal fluid and hydrocephalus、Alzheimer's disease research and treatments、Intracerebral and Subarachnoid Hemorrhage Research

BACKGROUND: 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. METHODS: 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 tomograp...