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Secretion of Pathological Tau Via an Unconventional, Non-vesicular Mechanism

19 Pages Posted: 7 Jan 2019 Sneak Peek Status: Published

See all articles by Maria Merezhko

Maria Merezhko

University of Helsinki - Neuroscience Center

Cecilia A. Brunello

University of Helsinki - Neuroscience Center

Xu Yan

University of Helsinki - Neuroscience Center

Helena Vihinen

University of Helsinki - Electron Microscopy Unit

Eija Jokitalo

University of Helsinki - Electron Microscopy Unit

Riikka-Liisa Uronen

University of Helsinki - Neuroscience Center

Henri J. Huttunen

University of Helsinki - Neuroscience Center

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Abstract

Cerebral accumulation of Tau protein aggregates, in the form of neurofibrillary tangles, is a pathological hallmark of numerous neurodegenerative disorders including Alzheimer's disease. In these tauopathies, Tau forms inclusions that spread throughout the brain via a cell-to-cell transmission process that includes cellular secretion and uptake of pathological Tau, followed by templated misfolding of normal Tau in recipient cells. The mechanism of Tau secretion remains poorly understood. Here we show that Tau is secreted independently of membrane trafficking or ATP, and that Tau is clustered in sub-plasma membrane microdomains. Tau secretion is decreased when levels of cholesterol or sphingomyelin on the plasma membrane are lowered, or by increasing the levels of omega-3 fatty acid docosahexanoic acid, indicating that plasma membrane lipids and biophysical properties play an important role in Tau secretion. Cell surface heparan sulphate proteoglycans support Tau secretion, possibly by facilitating its release after membrane penetration. Several Tau aggregation inhibitors reduce Tau secretion, with epigallocatechin-3-gallate showing the most potent effects. Together, these results suggest that Tau is released by an unconventional secretory mechanism that involves hyperphosphorylation and oligomerization, and that membrane interaction may help Tau to acquire properties that allow its escape from cells directly through the plasma membrane.

Suggested Citation

Merezhko, Maria and Brunello, Cecilia A. and Yan, Xu and Vihinen, Helena and Jokitalo, Eija and Uronen, Riikka-Liisa and Huttunen, Henri J., Secretion of Pathological Tau Via an Unconventional, Non-vesicular Mechanism (2018). Available at SSRN: https://ssrn.com/abstract=3188432 or http://dx.doi.org/10.2139/ssrn.3188432
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Maria Merezhko

University of Helsinki - Neuroscience Center

Helsinki, FIN-00014
Finland

Cecilia A. Brunello

University of Helsinki - Neuroscience Center

Helsinki, FIN-00014
Finland

Xu Yan

University of Helsinki - Neuroscience Center

Helsinki, FIN-00014
Finland

Helena Vihinen

University of Helsinki - Electron Microscopy Unit

Helsinki, FIN-00014
Finland

Eija Jokitalo

University of Helsinki - Electron Microscopy Unit

Helsinki, FIN-00014
Finland

Riikka-Liisa Uronen

University of Helsinki - Neuroscience Center

Helsinki, FIN-00014
Finland

Henri J. Huttunen (Contact Author)

University of Helsinki - Neuroscience Center ( email )

Helsinki, FIN-00014
Finland

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