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Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways

T. Wassmer, L. Evans, G. Fraser, J. Smith, M. Perkinton, A. Billinton, F.J. Livesey
doi: https://doi.org/10.1101/168294
T. Wassmer
1Talisman Therapeutics, Babraham Research Campus, Cambridge, CB22 3AT
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L. Evans
2Gurdon Institute and Department of Biochemistry, University of Cambridge, CB2 1QN
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G. Fraser
3AstraZeneca Neuroscience Innovative Medicines and Early Development, Granta Park, Cambridge, CB21 6GH
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J. Smith
1Talisman Therapeutics, Babraham Research Campus, Cambridge, CB22 3AT
2Gurdon Institute and Department of Biochemistry, University of Cambridge, CB2 1QN
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M. Perkinton
3AstraZeneca Neuroscience Innovative Medicines and Early Development, Granta Park, Cambridge, CB21 6GH
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A. Billinton
3AstraZeneca Neuroscience Innovative Medicines and Early Development, Granta Park, Cambridge, CB21 6GH
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F.J. Livesey
1Talisman Therapeutics, Babraham Research Campus, Cambridge, CB22 3AT
2Gurdon Institute and Department of Biochemistry, University of Cambridge, CB2 1QN
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  • For correspondence: rick@gurdon.cam.ac.uk
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Abstract

A current working model is that Alzheimer's disease actively spreads from diseased to healthy neurons, mediated by transfer of extracellular, abnormal, disease-specific forms of the microtubule-associated protein tau. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia, or reflects a constitutive biological process. We report two mechanisms of entry of monomeric tau to neurons: a rapid early dynamin-dependent phase, and a second, slower actin-dependent phase, suggesting that monomeric tau enters neurons via rapid saturable clathrin-mediated endocytosis and also by bulk endocytosis. Aggregated tau entry is independent of actin polymerisation and largely dynamin dependent, consistent with clathrin-mediated endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate tau entry into neurons, with tau carrying antibody with it into neurons, indicating that antibody binding is insufficient to prevent neuronal tau entry.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted July 25, 2017.
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Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways
T. Wassmer, L. Evans, G. Fraser, J. Smith, M. Perkinton, A. Billinton, F.J. Livesey
bioRxiv 168294; doi: https://doi.org/10.1101/168294
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Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways
T. Wassmer, L. Evans, G. Fraser, J. Smith, M. Perkinton, A. Billinton, F.J. Livesey
bioRxiv 168294; doi: https://doi.org/10.1101/168294

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