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
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.
