Editors' ChoiceTAUOPATHIES

The lymphatic route of TAU

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Science Translational Medicine  13 Mar 2019:
Vol. 11, Issue 483, eaax0769
DOI: 10.1126/scitranslmed.aax0769

Abstract

The brain lymphatic system contributes to TAU clearance in mice.

An inability to clear disease-associated proteins from the brain is thought to contribute to pathogenesis in neurodegenerative diseases. In Alzheimer’s disease and other tauopathies, spread of TAU seeds through the brain and the eventual accumulation of insoluble aggregates is a proposed mechanism of progressive neurodegeneration. Understanding the mechanisms by which the brain clears these proteins and how this process fails in disease might help the development of effective therapies. The recently discovered lymphatic system of the brain, residing within the dura of the meninges, has been shown to play a leading role in draining macromolecules from the brain to the cerebrospinal fluid; however, its role in clearing TAU is not yet defined.

Patel et al. used a near-infrared (NIR) imaging technique, fluorescence molecular tomography (FMT), to investigate removal of extracellular TAU by the lymphatic system in a mouse model. The authors injected MIR-labeled TAU and tracked the clearance in real time. The results showed that wild type mice cleared TAU faster than transgenic mice lacking dural lymphatics. Transgenic mice were still able to clear TAU, albeit demonstrating impairment, indicating that TAU clearance is not exclusively mediated by the lymphatic pathway. As manipulation of the mouse during FMT was minimal, the authors were able to collect serum samples in parallel to monitor TAU clearance from the brain into the blood. Furthermore, mice could be longitudinally monitored. In the context of neurodegenerative diseases, which take months to develop, this offers a chance to understand when changes occur and how they influence disease evolution.

The question of whether reduced clearance of extracellular TAU by the dural lymphatic system contributes to TAUopathies and, if so, what degree of clearance impairment will elicit pathological changes remains to be answered. The NIR system offers an opportunity to answer this and many other exciting questions. Does age affect this clearance mechanism? Is aggregated TAU cleared differently from its soluble counterpart? If this clearance system proves critical for TAU accumulation in disease, understanding how to stimulate an increased rate of clearance might have therapeutic applications.

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