Fully co-factor-free ClearTau platform produces seeding-competent Tau fibrils for reconstructing pathological Tau aggregates

Galina Limorenko, Meltem Tatli, Rajasekhar Kolla, Sergey Nazarov, Marie-Theres Weil, David C. Schöndorf, Daniela Geist, Peter Reinhardt, Dagmar E. Ehrnhoefer, Henning Stahlberg, Laura Gasparini and Hilal A. Lashuel ()
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Galina Limorenko: Ecole Polytechnique Fédérale de Lausanne
Meltem Tatli: Ecole Polytechnique Fédérale de Lausanne
Rajasekhar Kolla: Ecole Polytechnique Fédérale de Lausanne
Sergey Nazarov: Ecole Polytechnique Fédérale de Lausanne
Marie-Theres Weil: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse
David C. Schöndorf: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse
Daniela Geist: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse
Peter Reinhardt: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse
Dagmar E. Ehrnhoefer: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse
Henning Stahlberg: Ecole Polytechnique Fédérale de Lausanne
Laura Gasparini: Neuroscience Discovery, AbbVie Deutschland GmbH & Co KG, Knollstrasse
Hilal A. Lashuel: Ecole Polytechnique Fédérale de Lausanne

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Tau protein fibrillization is implicated in the pathogenesis of several neurodegenerative diseases collectively known as Tauopathies. For decades, investigating Tau fibrillization in vitro has required the addition of polyanions or other co-factors to induce its misfolding and aggregation, with heparin being the most commonly used. However, heparin-induced Tau fibrils exhibit high morphological heterogeneity and a striking structural divergence from Tau fibrils isolated from Tauopathies patients’ brains at ultra- and macro-structural levels. To address these limitations, we developed a quick, cheap, and effective method for producing completely co-factor-free fibrils from all full-length Tau isoforms and mixtures thereof. We show that Tau fibrils generated using this ClearTau method – ClearTau fibrils - exhibit amyloid-like features, possess seeding activity in biosensor cells and hiPSC-derived neurons, retain RNA-binding capacity, and have morphological properties and structures more reminiscent of the properties of the brain-derived Tau fibrils. We present the proof-of-concept implementation of the ClearTau platform for screening Tau aggregation-modifying compounds. We demonstrate that these advances open opportunities to investigate the pathophysiology of disease-relevant Tau aggregates and will facilitate the development of Tau pathology-targeting and modifying therapies and PET tracers that can distinguish between different Tauopathies.

Date: 2023
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DOI: 10.1038/s41467-023-39314-7

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