Super-resolution imaging unveils the self-replication of tau aggregates upon seeding

Eleni Dimou; Taxiarchis Katsinelos; Georg Meisl; Benjamin J. Tuck; Sophie Keeling; Annabel E. Smith; Eric Hidari; Jeff Y.L. Lam; Melanie Burke; Sofia Lövestam; Rohan T. Ranasinghe; William A. McEwan; David Klenerman

Cell Reports (Jul 2023)

Super-resolution imaging unveils the self-replication of tau aggregates upon seeding

Eleni Dimou,
Taxiarchis Katsinelos,
Georg Meisl,
Benjamin J. Tuck,
Sophie Keeling,
Annabel E. Smith,
Eric Hidari,
Jeff Y.L. Lam,
Melanie Burke,
Sofia Lövestam,
Rohan T. Ranasinghe,
William A. McEwan,
David Klenerman

Affiliations

Eleni Dimou: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK; Corresponding author
Taxiarchis Katsinelos: UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
Georg Meisl: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Benjamin J. Tuck: UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK
Sophie Keeling: UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK
Annabel E. Smith: UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK
Eric Hidari: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK
Jeff Y.L. Lam: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK
Melanie Burke: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK
Sofia Lövestam: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
Rohan T. Ranasinghe: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK
William A. McEwan: UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK
David Klenerman: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge CB2 0AH, UK; Corresponding author

Journal volume & issue: Vol. 42, no. 7
p. 112725

Abstract

Read online

Summary: Tau is a soluble protein interacting with tubulin to stabilize microtubules. However, under pathological conditions, it becomes hyperphosphorylated and aggregates, a process that can be induced by treating cells with exogenously added tau fibrils. Here, we employ single-molecule localization microscopy to resolve the aggregate species formed in early stages of seeded tau aggregation. We report that entry of sufficient tau assemblies into the cytosol induces the self-replication of small tau aggregates, with a doubling time of 5 h inside HEK cells and 1 day in murine primary neurons, which then grow into fibrils. Seeding occurs in the vicinity of the microtubule cytoskeleton, is accelerated by the proteasome, and results in release of small assemblies into the media. In the absence of seeding, cells still spontaneously form small aggregates at lower levels. Overall, our work provides a quantitative picture of the early stages of templated seeded tau aggregation in cells.

CP: Cell biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords