Distinct conformations, aggregation and cellular internalization of different tau strains

T.K. Karikari, David A Nagel, Alastair Grainger, Charlotte Clarke-Bland, James Crowe, Eric J Hill, Kevin G. Moffat

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Article number296
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
Publication statusPublished - 9 Jul 2019

Fingerprint

Frontotemporal Dementia
Tauopathies
Induced Pluripotent Stem Cells
tau Proteins
Mutation
Carisoprodol
Neurites
Nuclear Proteins
Endocytosis
Neuroblastoma
Neurodegenerative Diseases
Heparin
Cytoplasm
Animal Models
Neurons
K-18 conjugate
Brain
Proteins

Bibliographical note

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.

Keywords

  • Alzheimer’s disease
  • Cellular internalization
  • Frontotemporal dementia
  • Induced pluripotent stem cell-derived neurons
  • MAPT mutations
  • Nuclear tau
  • Oligomer
  • Tau protein

Cite this

Karikari, T.K. ; Nagel, David A ; Grainger, Alastair ; Clarke-Bland, Charlotte ; Crowe, James ; Hill, Eric J ; Moffat, Kevin G. / Distinct conformations, aggregation and cellular internalization of different tau strains. In: Frontiers in Cellular Neuroscience. 2019 ; Vol. 13.
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Distinct conformations, aggregation and cellular internalization of different tau strains. / Karikari, T.K.; Nagel, David A; Grainger, Alastair; Clarke-Bland, Charlotte; Crowe, James; Hill, Eric J; Moffat, Kevin G.

In: Frontiers in Cellular Neuroscience, Vol. 13, 296, 09.07.2019.

Research output: Contribution to journalArticle

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AU - Karikari, T.K.

AU - Nagel, David A

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AU - Crowe, James

AU - Hill, Eric J

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AB - 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.

KW - Alzheimer’s disease

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KW - Induced pluripotent stem cell-derived neurons

KW - MAPT mutations

KW - Nuclear tau

KW - Oligomer

KW - Tau protein

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