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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月17日

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

摘要

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.