Dural lymphatics regulate clearance of extracellular tau from the CNS

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dc.contributor.author Patel, Tirth K
dc.contributor.author Habimana-Griffin, LeMoyne
dc.contributor.author Gao, Xuefeng
dc.contributor.author Xu, Baogang
dc.contributor.author Achilefu, Samuel
dc.contributor.author Alitalo, Kari
dc.contributor.author McKee, Celia A
dc.contributor.author Sheehan, Patrick W
dc.contributor.author Musiek, Erik S
dc.contributor.author Xiong, Chengjie
dc.contributor.author Coble, Dean
dc.contributor.author Holtzman, David M
dc.date.accessioned 2019-03-03T04:14:47Z
dc.date.available 2019-03-03T04:14:47Z
dc.date.issued 2019-02-27
dc.identifier.citation Molecular Neurodegeneration. 2019 Feb 27;14(1):11
dc.identifier.uri http://hdl.handle.net/10138/299820
dc.description.abstract Abstract 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 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. Results 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. Conclusions 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.
dc.language.iso eng
dc.publisher BioMed Central
dc.subject Alzheimer’s disease
dc.subject Tau
dc.subject Tauopathy
dc.subject Neurodegeneration
dc.subject Dural lymphatic system
dc.subject Glymphatic system
dc.subject Tau clearance
dc.subject Tau imaging
dc.title Dural lymphatics regulate clearance of extracellular tau from the CNS en
dc.date.updated 2019-03-03T04:14:47Z
dc.type.uri http://purl.org/eprint/entityType/ScholarlyWork
dc.type.uri http://purl.org/eprint/entityType/Expression
dc.type.uri http://purl.org/eprint/type/JournalArticle
dc.rights.copyrightholder The Author(s).

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