Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways.
Authors
Evans, Lewis
Wassmer, Thomas
Fraser, Graham
Perkinton, Michael
Billinton, Andrew
Publication Date
2018-03-27Journal Title
Cell Rep
ISSN
2211-1247
Publisher
Elsevier BV
Volume
22
Issue
13
Pages
3612-3624
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Evans, L., Wassmer, T., Fraser, G., Smith, J., Perkinton, M., Billinton, A., & Livesey, F. (2018). Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways.. Cell Rep, 22 (13), 3612-3624. https://doi.org/10.1016/j.celrep.2018.03.021
Abstract
In Alzheimer's disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. 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 entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon.
Keywords
Cerebral Cortex, Neurons, Humans, Dynamins, tau Proteins, Endocytosis, Phosphorylation, Induced Pluripotent Stem Cells, Protein Aggregation, Pathological, Human Embryonic Stem Cells
Sponsorship
Wellcome Trust (101052/Z/13/Z)
Alzheimer's Research UK (ARUK-SCRC2014-1)
Medical Research Council (MR/N013255/1)
Wellcome Trust (203144/Z/16/Z)
Cancer Research UK (C6946/A24843)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1016/j.celrep.2018.03.021
This record's URL: https://www.repository.cam.ac.uk/handle/1810/276985
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