Distinct conformations, aggregation and cellular internalization of different tau strains


The inter-cellular propagation of tau aggregates in several neurodegenerative diseases involves, in part, recurring cycles of extracellular tau uptake, initiation of endogenous tau aggregation, and extracellular release of at least part of this protein complex. However, human brain tau extracts from diverse tauopathies exhibit variant or “strain” specificity in inducing inter-cellular propagation in both cell and animal models. It is unclear if these distinctive properties are affected by disease-specific differences in aggregated tau conformation and structure. We have used a combined structural and cell biological approach to study if two frontotemporal dementia (FTD)-associated pathologic mutations, V337M and N279K, affect the aggregation, conformation and cellular internalization of the tau four-repeat domain (K18) fragment. In both heparin-induced and native-state aggregation experiments, each FTD variant formed soluble and fibrillar aggregates with remarkable morphological and immunological distinctions from the wild type (WT) aggregates. Exogenously-applied oligomers of the FTD tau-K18 variants (V337M and N279K) were significantly more efficiently taken up by SH-SY5Y neuroblastoma cells than WT tau-K18, suggesting mutation-induced changes in cellular internalization. However, shared internalization mechanisms were observed: endocytosed oligomers were distributed in the cytoplasm and nucleus of SH-SY5Y cells and the neurites and soma of human induced pluripotent stem cell-derived neurons where they co-localized with endogenous tau and the nuclear protein nucleolin. Altogether, evidence of conformational and aggregation differences between WT and disease-mutated tau K18 is demonstrated, which may explain their distinct cellular internalization potencies. These findings may account for critical aspects of the molecular pathogenesis of tauopathies involving WT and mutated tau.

Publication DOI: https://doi.org/10.3389/fncel.2019.00296
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences
College of Health & Life Sciences > Clinical and Systems Neuroscience
Additional Information: Copyright: © 2019 Karikari, Nagel, Grainger, Clarke-Bland, Crowe, Hill and Moffat. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Uncontrolled Keywords: Alzheimer’s disease,Cellular internalization,Frontotemporal dementia,Induced pluripotent stem cell-derived neurons,MAPT mutations,Nuclear tau,Oligomer,Tau protein,Cellular and Molecular Neuroscience
Publication ISSN: 1662-5102
Last Modified: 16 May 2024 07:13
Date Deposited: 19 Aug 2019 09:30
Full Text Link:
Related URLs: https://www.fro ... .00296/abstract (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2019-07-09
Accepted Date: 2019-06-18
Authors: Karikari, T.K.
Nagel, David A (ORCID Profile 0000-0002-9055-1775)
Grainger, Alastair
Clarke-Bland, Charlotte (ORCID Profile 0000-0001-5776-2733)
Crowe, James
Hill, Eric J (ORCID Profile 0000-0002-9419-1500)
Moffat, Kevin G.



Version: Published Version

License: Creative Commons Attribution

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