Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding

Neuronal aggregates of Tau are a hallmark of Alzheimer's disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions, while some have co-aggregates of the two proteins. The presence of such co-aggregates is associated with increased disease severity, although whether there is a causal relationship remains unclear. Here, we demonstrate that Tau and TDP-43 mutually promote each other's condensation through direct interaction in vitro, forming irregularly-shaped or multiphasic co-condensates with lower TDP-43 mobility, but higher Tau mobility. While Tau promotes TDP-43 aggregation in vitro, TDP-43 suppresses formation of Tau fibrils and instead causes formation of oligomeric Tau and Tau/TDP-43 species. These co-assemblies hinder Tau seeding in a biosensor assay specific for proteopathic Tau seeds. Consistent with these data, insoluble material extracted from AD patient brains with Tau/TDP-43 co-aggregates exhibits reduced Tau seeding compared to AD patient brains with Tau aggregates only. In contrast, patient-derived extracts from AD patient brains with Tau/TDP-43 co-aggregates are highly potent in seeding new TDP-43 aggregates in a TDP-43 reporter cell line. Our results suggest that direct interaction between TDP-43 and Tau may suppress Tau pathology, while promoting TDP-43 pathology in Alzheimer's disease patients.

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Publication Details

Journal
The EMBO Journal
Published
2025-10-17
DOI
https://doi.org/10.1038/s44318-025-00590-2
Citations
5
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
5.82
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Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding

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5 citations
The EMBO Journal
Alzheimer's disease research and treatments
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article

Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding

Ali Rezaei, Susanne Wegmann, Fridolin Kielisch, Dieter Edbauer, Janine Hochmair, Saskia Hutten, Markus Zweckstetter, Tammaryn Lashley, Weijia Zhong, Martina Schifferer, Dorothee Dormann, Viktoria Ruf, Rithika Sankar, Anusha B. Gopalan, Mikael Simons, Magdalini Polymenidou, Federico Uliana, Francesca Simonetti, Carla Schmidt, Henrick Riemenschneider, Lisa Marie Ramirez
article en
5 citations

Abstract

Neuronal aggregates of Tau are a hallmark of Alzheimer's disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions, while some have co-aggregates of the two proteins. The presence of such co-aggregates is associated with increased disease severity, although whether there is a causal relationship remains unclear. Here, we demonstrate that Tau and TDP-43 mutually promote each other's condensation through direct interaction in vitro, forming irregularly-shaped or multiphasic co-condensates with lower TDP-43 mobility, but higher Tau mobility. While Tau promotes TDP-43 aggregation in vitro, TDP-43 suppresses formation of Tau fibrils and instead causes formation of oligomeric Tau and Tau/TDP-43 species. These co-assemblies hinder Tau seeding in a biosensor assay specific for proteopathic Tau seeds. Consistent with these data, insoluble material extracted from AD patient brains with Tau/TDP-43 co-aggregates exhibits reduced Tau seeding compared to AD patient brains with Tau aggregates only. In contrast, patient-derived extracts from AD patient brains with Tau/TDP-43 co-aggregates are highly potent in seeding new TDP-43 aggregates in a TDP-43 reporter cell line. Our results suggest that direct interaction between TDP-43 and Tau may suppress Tau pathology, while promoting TDP-43 pathology in Alzheimer's disease patients.

The EMBO JournalVol. 44(24)
Johannes Gutenberg University Mainz (DE), University of Zurich (CH), German Center for Neurodegenerative Diseases (DE), LMU Klinikum (DE), University Medical Center of the Johannes Gutenberg University Mainz (DE), Max Planck Institute for the Study of Religious and Ethnic Diversity (DE), Munich Cluster for Systems Neurology (DE), Max Planck Institute of Experimental Medicine (DE), National Hospital for Neurology and Neurosurgery (GB), Urologische Klinik München (DE), Institute of Molecular Biology (DE), University College London (GB), Ludwig-Maximilians-Universität München (DE)
Openalex Percentile: Top 4%
Alzheimer's disease research and treatments
5.82
DOIOpen Access PDFOpenAlex
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