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

Simonetti, Francesca, Zhong, Weijia, Hutten, Saskia, Uliana, Federico, Schifferer, Martina, Rezaei, Ali, Ramirez, Lisa Marie, Hochmair, Janine, Sankar, Rithika, Gopalan, Anusha, Kielisch, Fridolin, Riemenschneider, Henrick, Ruf, Viktoria, Schmidt, Carla, Simons, Mikael, Zweckstetter, Markus, Wegmann, Susanne, Lashley, Tammaryn, Polymenidou, Magdalini, Edbauer, Dieter, Dormann, Dorothee·2025·The EMBO Journal
DOI 10.1038/s44318-025-00590-2PMC PMC12706024
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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.

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Figure 1 Tau, but not MBP or α-synuclein, causes formation of large irregular TDP-43 condensates. (A) Scheme of TDP-43 phase separation assay upon TEV-cleavage of the MBP-solubility tag; created with BioRender.com. (B) Time series of Alexa488-labeled TDP-43 condensate formation (8 µM) in presence or absence of DyLight650-labeled Tau (8 µM), from 20 to 45 min after cleavage with TEV protease; images represent frames of Movies EV1 and EV2; scale bar: 10 µm. (C) Confocal images of Alexa488-labeled TDP-43 condensates (5 µM) in presence of unlabeled Tau, MBP, or α-synuclein (2, 5 or 10 µM), 30 min after TEV-cleavage. Scale bar: 15 µm in overview and 8 µm in inset. (D) Graphs showing number of particles, circularity, and size of the TDP-43 condensates. Individual data points from (n = 2) biological replicates are shown. (E) Representative FRAP images of Alexa488-labeled TDP-43 condensates (15 µM) at the indicated time points, in the absence or presence of equimolar unlabeled Tau, MBP, or α-synuclein, within 15 min of TEV protease addition. Dotted box indicates the bleached area (half of the condensate). Scale bar: 1 µm. (F) FRAP recovery curves following half-bleaching of Alexa488-labeled TDP-43 condensates in absence or presence of Tau, MBP, and α-synuclein. Data represent ± SEM from 11 to 12 individual condensates analyzed per condition in four biological replicates. ***P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to TDP-43 only condition; significant difference was determined by calculating the area under the curve (AUC) for each condition.
Figure 1 Tau, but not MBP or α-synuclein, causes formation of large irregular TDP-43 condensates. (A) Scheme of TDP-43 phase separation assay upon TEV-cleavage of the MBP-solubility tag; created with BioRender.com. (B) Time series of Alexa488-labeled TDP-43 condensate formation (8 µM) in presence or absence of DyLight650-labeled Tau (8 µM), from 20 to 45 min after cleavage with TEV protease; images represent frames of Movies EV1 and EV2; scale bar: 10 µm. (C) Confocal images of Alexa488-labeled TDP-43 condensates (5 µM) in presence of unlabeled Tau, MBP, or α-synuclein (2, 5 or 10 µM), 30 min after TEV-cleavage. Scale bar: 15 µm in overview and 8 µm in inset. (D) Graphs showing number of particles, circularity, and size of the TDP-43 condensates. Individual data points from (n = 2) biological replicates are shown. (E) Representative FRAP images of Alexa488-labeled TDP-43 condensates (15 µM) at the indicated time points, in the absence or presence of equimolar unlabeled Tau, MBP, or α-synuclein, within 15 min of TEV protease addition. Dotted box indicates the bleached area (half of the condensate). Scale bar: 1 µm. (F) FRAP recovery curves following half-bleaching of Alexa488-labeled TDP-43 condensates in absence or presence of Tau, MBP, and α-synuclein. Data represent ± SEM from 11 to 12 individual condensates analyzed per condition in four biological replicates. ***P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to TDP-43 only condition; significant difference was determined by calculating the area under the curve (AUC) for each condition.CC BY · PubMed Central
Figure EV1 pTau, but not the Tau N-terminal domain or repeat domain, enriches in TDP-43 condensates and aggregates. (A) Scheme of recombinant Tau variants with their respective net charges; created with BioRender.com. (B) Coomassie-stained SDS-PAGE gel showing the molecular sizes of Tau, phosphorylated Tau (pTau), Tau N-terminal domain (Tau-NTD), and the Tau-RD fragment (R1–R4 repeat domains). (C) Confocal microscopy images of Alexa488-labeled TDP-43 (5 µM) in absence or presence of DyLight650-labeled Tau, pTau, Tau-NTD, or Tau-RD in a phase separation assay. Scale bar: 15 µm in overview and 3 µm in inset. (D) Colocalization of Tau, pTau, Tau-NTD, or Tau-RD within TDP-43 condensates quantified by measuring the area of condensates exhibiting overlapping green and far-red signals. Quantification was performed across (n = 3) biological replicates, and bar graphs show values ± SEM. (E) Confocal microscopy images of Alexa488-labeled TDP-43 (5 µM) in absence or presence of DyLight650-labeled Tau, pTau, Tau-NTD, or Tau-RD in an aggregation assay. Scale bar: 15 µm in overview and 3 µm in inset. (F) Colocalization of Tau, pTau, Tau-NTD, or Tau-RD within TDP-43 aggregates quantified by measuring the area of aggregates exhibiting overlapping green and far-red signals. Quantification was performed across (n = 3) biological replicates, and bar graphs show values ± SEM.
Figure EV1 pTau, but not the Tau N-terminal domain or repeat domain, enriches in TDP-43 condensates and aggregates. (A) Scheme of recombinant Tau variants with their respective net charges; created with BioRender.com. (B) Coomassie-stained SDS-PAGE gel showing the molecular sizes of Tau, phosphorylated Tau (pTau), Tau N-terminal domain (Tau-NTD), and the Tau-RD fragment (R1–R4 repeat domains). (C) Confocal microscopy images of Alexa488-labeled TDP-43 (5 µM) in absence or presence of DyLight650-labeled Tau, pTau, Tau-NTD, or Tau-RD in a phase separation assay. Scale bar: 15 µm in overview and 3 µm in inset. (D) Colocalization of Tau, pTau, Tau-NTD, or Tau-RD within TDP-43 condensates quantified by measuring the area of condensates exhibiting overlapping green and far-red signals. Quantification was performed across (n = 3) biological replicates, and bar graphs show values ± SEM. (E) Confocal microscopy images of Alexa488-labeled TDP-43 (5 µM) in absence or presence of DyLight650-labeled Tau, pTau, Tau-NTD, or Tau-RD in an aggregation assay. Scale bar: 15 µm in overview and 3 µm in inset. (F) Colocalization of Tau, pTau, Tau-NTD, or Tau-RD within TDP-43 aggregates quantified by measuring the area of aggregates exhibiting overlapping green and far-red signals. Quantification was performed across (n = 3) biological replicates, and bar graphs show values ± SEM.CC BY · PubMed Central
Figure 2 TDP-43 and Tau directly interact in condensates formed in vitro. (A) Scheme of XL-MS experiment; created with BioRender.com. (B) Inter-protein crosslinked peptides identified for TDP-43 + Tau and TDP-43 + MBP under bulk and pellet conditions following condensate induction (n = 3) independent replicates. Only crosslinks detected in at least two out of three replicates, with a peptide-spectrum match (PSM) false discovery rate (FDR) < 1% from light and heavy isotope-labeled DSS crosslinking experiments, were included. Inter-protein crosslinks are shown in grey, with line thickness proportional to the spectral count (i.e., relative abundance).
Figure 2 TDP-43 and Tau directly interact in condensates formed in vitro. (A) Scheme of XL-MS experiment; created with BioRender.com. (B) Inter-protein crosslinked peptides identified for TDP-43 + Tau and TDP-43 + MBP under bulk and pellet conditions following condensate induction (n = 3) independent replicates. Only crosslinks detected in at least two out of three replicates, with a peptide-spectrum match (PSM) false discovery rate (FDR) < 1% from light and heavy isotope-labeled DSS crosslinking experiments, were included. Inter-protein crosslinks are shown in grey, with line thickness proportional to the spectral count (i.e., relative abundance).CC BY · PubMed Central
Figure 3 Tau, but not MBP or α-synuclein, promotes TDP-43 aggregation. (A) Scheme of TDP-43 aggregation assay for SDD-AGE experiment; created with BioRender.com. (B) SDD-AGE of TDP-43-MBP (2 µM) in the presence of the indicated protein (2 µM) after agitation and incubation for the presented time period (h = hours, d = days); TDP-43 was visualized by immunoblotting and the middle vertical black line divides two blots which derive from the same experiment and were processed in parallel. °°° = high molecular weight (HMW) species, °° = oligomers and ° = monomers. (C) Quantification of band intensities of the high molecular weight species from (n = 3) biological replicates, normalized to the timepoint 0; values show the mean ± SEM; **P = 0.0039 and *P = 0.0273 by two-way ANOVA with Dunnett´s multiple comparison test to TDP-43-MBP only condition at the respective time points (0, 1 h, 2 h, 8 h, 1 d, 2 d, 6 d). (D) Scheme of Alexa488-labeled TDP-43 aggregation for confocal imaging; created with BioRender.com. (E) Confocal images of Alexa488-labeled TDP-43 aggregates (10 µM) in presence of unlabeled Tau, MBP or α-synuclein (5, 10 or 20 µM) 2 h after the agitation step. Scale bar: 20 µm in overview and 15 µm in inset. (F) Quantification of the total area covered by the TDP-43 aggregates (Aggr. area). Bar graph shows the mean of (n = 4) biological replicates ± SD. ***P = 0.0008 and *P = 0.0255 by one-way ANOVA with Dunnett´s multiple comparison test to TDP-43 only condition.
Figure 3 Tau, but not MBP or α-synuclein, promotes TDP-43 aggregation. (A) Scheme of TDP-43 aggregation assay for SDD-AGE experiment; created with BioRender.com. (B) SDD-AGE of TDP-43-MBP (2 µM) in the presence of the indicated protein (2 µM) after agitation and incubation for the presented time period (h = hours, d = days); TDP-43 was visualized by immunoblotting and the middle vertical black line divides two blots which derive from the same experiment and were processed in parallel. °°° = high molecular weight (HMW) species, °° = oligomers and ° = monomers. (C) Quantification of band intensities of the high molecular weight species from (n = 3) biological replicates, normalized to the timepoint 0; values show the mean ± SEM; **P = 0.0039 and *P = 0.0273 by two-way ANOVA with Dunnett´s multiple comparison test to TDP-43-MBP only condition at the respective time points (0, 1 h, 2 h, 8 h, 1 d, 2 d, 6 d). (D) Scheme of Alexa488-labeled TDP-43 aggregation for confocal imaging; created with BioRender.com. (E) Confocal images of Alexa488-labeled TDP-43 aggregates (10 µM) in presence of unlabeled Tau, MBP or α-synuclein (5, 10 or 20 µM) 2 h after the agitation step. Scale bar: 20 µm in overview and 15 µm in inset. (F) Quantification of the total area covered by the TDP-43 aggregates (Aggr. area). Bar graph shows the mean of (n = 4) biological replicates ± SD. ***P = 0.0008 and *P = 0.0255 by one-way ANOVA with Dunnett´s multiple comparison test to TDP-43 only condition.CC BY · PubMed Central
Figure 4 TDP-43-MBP, but not MBP or α-synuclein, causes the formation of large, amorphous Tau condensates in vitro. (A) Schematic representation of Tau phase separation assay; created with BioRender.com. (B) Confocal microscopy images of 4 µM DyLight488-labeled Tau only, Alexa633-labeled TDP-43-MBP only, and DyLight488-labeled Tau in equimolar presence of Alexa633-labeled TDP-43-MBP, DyLight650-labeled MBP or Lumidyne650-labeled α-synuclein at the indicated timepoints (1, 4, 24 h). Scale bar: 20 µm in overview and 5 µm in inset. Images shown are representative images from one experiment out of 6 experimental replicates, all of which yielded similar results. (C) Representative FRAP images of DyLight488-labeled Tau condensates (15 µM) at the indicated time points, in the absence or presence of equimolar unlabeled TDP-43-MBP, MBP, or α-synuclein, within 1.5 h of 10% PEG addition. Dotted circle indicates the bleached area (point bleach). Scale bar: 1 µm. (D) Parameters of exponential recovery models fitted to FRAP curves of DyLight488-labeled Tau condensates in absence or presence of TDP-43-MBP, MBP, and α-synuclein. Error bars represent 95% confidence intervals based on 14–16 curves per condition, collected across four biological replicates. The center of error bars represents the estimated values. **P = 0.001744 and ****P = 2e-20 by t tests of regression parameters (Wald-type tests). (E) FRAP curves following point-bleaching of DyLight488-labeled Tau condensates in absence or presence of TDP-43-MBP, MBP, and α-synuclein. Points and error bars represent mean ± SEM from 14 to 16 individual condensates per condition, collected across four biological replicates. Solid lines show exponential recovery model fits used for statistical analysis in (D).
Figure 4 TDP-43-MBP, but not MBP or α-synuclein, causes the formation of large, amorphous Tau condensates in vitro. (A) Schematic representation of Tau phase separation assay; created with BioRender.com. (B) Confocal microscopy images of 4 µM DyLight488-labeled Tau only, Alexa633-labeled TDP-43-MBP only, and DyLight488-labeled Tau in equimolar presence of Alexa633-labeled TDP-43-MBP, DyLight650-labeled MBP or Lumidyne650-labeled α-synuclein at the indicated timepoints (1, 4, 24 h). Scale bar: 20 µm in overview and 5 µm in inset. Images shown are representative images from one experiment out of 6 experimental replicates, all of which yielded similar results. (C) Representative FRAP images of DyLight488-labeled Tau condensates (15 µM) at the indicated time points, in the absence or presence of equimolar unlabeled TDP-43-MBP, MBP, or α-synuclein, within 1.5 h of 10% PEG addition. Dotted circle indicates the bleached area (point bleach). Scale bar: 1 µm. (D) Parameters of exponential recovery models fitted to FRAP curves of DyLight488-labeled Tau condensates in absence or presence of TDP-43-MBP, MBP, and α-synuclein. Error bars represent 95% confidence intervals based on 14–16 curves per condition, collected across four biological replicates. The center of error bars represents the estimated values. **P = 0.001744 and ****P = 2e-20 by t tests of regression parameters (Wald-type tests). (E) FRAP curves following point-bleaching of DyLight488-labeled Tau condensates in absence or presence of TDP-43-MBP, MBP, and α-synuclein. Points and error bars represent mean ± SEM from 14 to 16 individual condensates per condition, collected across four biological replicates. Solid lines show exponential recovery model fits used for statistical analysis in (D).CC BY · PubMed Central
Figure EV2 Early intra-droplet structures appear at the initial stages of multiphasic Tau/TDP-43 co-condensate formation. (A–C) High resolution images using AiryScan of 1:1 DyLight488-labeled Tau with Alexa633-labeled TDP-43-MBP mixed condensates after 10 min (A), 2 h (B) or (C) 24 h incubation. Scale bar: 1 μm (A), 2 µm (B) or 10 µm (C). In (A), dotted lines show the origin of line profiles indicated on the right, demonstrating demixing of Tau and TDP-43 within the same condensate at early timepoints.
Figure EV2 Early intra-droplet structures appear at the initial stages of multiphasic Tau/TDP-43 co-condensate formation. (A–C) High resolution images using AiryScan of 1:1 DyLight488-labeled Tau with Alexa633-labeled TDP-43-MBP mixed condensates after 10 min (A), 2 h (B) or (C) 24 h incubation. Scale bar: 1 μm (A), 2 µm (B) or 10 µm (C). In (A), dotted lines show the origin of line profiles indicated on the right, demonstrating demixing of Tau and TDP-43 within the same condensate at early timepoints.CC BY · PubMed Central
Figure EV3 Distinct regions of TDP-43 contribute to Tau phase separation and the formation of multiphasic co-condensates. (A) Scheme of recombinant TDP-43 deletion mutants; created with BioRender.com. (B) Confocal microscopy images of 4 µM DyLight488-labeled Tau in equimolar presence of Alexa633-labeled TDP-43-WT-MBP, TDP-43-NTF-MBP, TDP-43-CTF-MBP, TDP-43-RRM, TDP-43-Δ1-101-MBP, or TDP-43-ΔCR-MBP at the indicated timepoints (1, 4, 24 h). Scale bar: 20 µm in overview and 2 µm in inset.
Figure EV3 Distinct regions of TDP-43 contribute to Tau phase separation and the formation of multiphasic co-condensates. (A) Scheme of recombinant TDP-43 deletion mutants; created with BioRender.com. (B) Confocal microscopy images of 4 µM DyLight488-labeled Tau in equimolar presence of Alexa633-labeled TDP-43-WT-MBP, TDP-43-NTF-MBP, TDP-43-CTF-MBP, TDP-43-RRM, TDP-43-Δ1-101-MBP, or TDP-43-ΔCR-MBP at the indicated timepoints (1, 4, 24 h). Scale bar: 20 µm in overview and 2 µm in inset.CC BY · PubMed Central
Figure 5 TDP-43 inhibits Tau fibrillization and promotes formation of small, oligomeric Tau and Tau/TDP-43 assemblies. (A) Schemes of Thioflavin T (ThT) and Tau fibrillization assays; created with BioRender.com. (B) Graph showing normalized ThT fluorescence measurements over 18 h ± SEM in (n > 3) biological replicates. *P = 0.0184 was determined by one-way ANOVA with Dunnett’s multiple comparison test, comparing each condition to Tau ΔK280 inly condition; significant difference was determined by calculating the area under the curve (AUC) for each condition. (C) TEM images of Tau, TDP-43-MBP, MBP or α-synuclein only (50 µM), and Tau in presence of TDP-43-MBP, MBP or α-synuclein, respectively, at equimolar ratio after 5 days incubation. Scale bars: 0.1 µm for Tau+TDP-43-MBP and TDP-43-MBP only, and 0.5 µm for Tau only, Tau+MBP, MBP only, Tau+α-synuclein and α-synuclein only. (D) Quantification of fibril length (µm) from (n ≥ 2) biological replicates and (n ≥ 5) technical replicates; values show the length of protein structures in µm and the bar graphs represent the mean ± SEM; ****P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to Tau only. (E) Quantification of the number of structures positive for either Tau antibody (Tau mAB, small black circle), TDP-43 antibody (TDP-43 mAB, large black circle), or both, quantified for Tau only, Tau + TDP-43-MBP, and TDP-43-MBP only conditions, following double gold immunostaining. Bar graph depict final values obtained by subtracting the number of positive structures observed in control samples stained with secondary antibodies only (see Appendix Fig. S6). Values were analyzed in n > 21 technical experiments. Scale bar: 0.1 µm and 0.03 µm in inset. (F) Representative images of Tau only, Tau + TDP-43-MBP, and TDP-43-MBP only stained with both Tau mAB and TDP-43 mAB.
Figure 5 TDP-43 inhibits Tau fibrillization and promotes formation of small, oligomeric Tau and Tau/TDP-43 assemblies. (A) Schemes of Thioflavin T (ThT) and Tau fibrillization assays; created with BioRender.com. (B) Graph showing normalized ThT fluorescence measurements over 18 h ± SEM in (n > 3) biological replicates. *P = 0.0184 was determined by one-way ANOVA with Dunnett’s multiple comparison test, comparing each condition to Tau ΔK280 inly condition; significant difference was determined by calculating the area under the curve (AUC) for each condition. (C) TEM images of Tau, TDP-43-MBP, MBP or α-synuclein only (50 µM), and Tau in presence of TDP-43-MBP, MBP or α-synuclein, respectively, at equimolar ratio after 5 days incubation. Scale bars: 0.1 µm for Tau+TDP-43-MBP and TDP-43-MBP only, and 0.5 µm for Tau only, Tau+MBP, MBP only, Tau+α-synuclein and α-synuclein only. (D) Quantification of fibril length (µm) from (n ≥ 2) biological replicates and (n ≥ 5) technical replicates; values show the length of protein structures in µm and the bar graphs represent the mean ± SEM; ****P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to Tau only. (E) Quantification of the number of structures positive for either Tau antibody (Tau mAB, small black circle), TDP-43 antibody (TDP-43 mAB, large black circle), or both, quantified for Tau only, Tau + TDP-43-MBP, and TDP-43-MBP only conditions, following double gold immunostaining. Bar graph depict final values obtained by subtracting the number of positive structures observed in control samples stained with secondary antibodies only (see Appendix Fig. S6). Values were analyzed in n > 21 technical experiments. Scale bar: 0.1 µm and 0.03 µm in inset. (F) Representative images of Tau only, Tau + TDP-43-MBP, and TDP-43-MBP only stained with both Tau mAB and TDP-43 mAB.CC BY · PubMed Central
Figure 6 TDP-43 inhibits Tau fibrillization via its N-Terminal fragment and suppresses Tau seeding in a Tau biosensor cells. (A) TEM images of Tau, TDP-43-MBP, TDP-43-NTF-MBP and TDP-43-CTF-MBP only (50 µM), and Tau in presence of TDP-43-MBP, TDP-43-NTF-MBP and TDP-43-CTF-MBP at equimolar ratio after 5 days incubation. Scale bars: 0.1 µm for TDP-43-MBP only, TDP-43-NTF-MBP only, TDP-43-CTF-MBP only, and Tau+TDP-43-CTF-MBP; 0.2 µm for Tau+TDP-43-MBP and Tau+TDP-43-NTF-MBP; 0.5 µm for Tau only. (B) Quantification of fibril length (µm) from (n ≥ 2) biological replicates and (n ≥ 5) technical replicates; values show the length of protein structures in µm and the bar graphs represent the mean ± SEM; ****P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to Tau only. (C) Scheme of Tau seeding assay in HEK293 GFP/YFP-TauRDP301S using in vitro generated Tau assemblies as seeds; created with BioRender.com. (D) Representative confocal images of cytosolic Tau aggregates (green) formed after seeding Tau biosensor cells with 5 days old recombinant Tau aggregates +/− TDP-43-MBP, TDP-43-NTF-MBP, TDP-43-CTF-MBP, MBP and α-synuclein. The ‘No seeds’ condition refers to cells treated with lipofectamine only. Scale bar: 70 µm in overview and 20 µm in inset. (E) Quantification of number of aggregates per cell. Bar graphs show the number of biological replicates ± SEM in (n = 5) biological replicates (different batches of cells on different days). *P = 0.0274 by one-way ANOVA Kruskal–Wallis test with Dunn´s multiple comparison test to Tau only condition.
Figure 6 TDP-43 inhibits Tau fibrillization via its N-Terminal fragment and suppresses Tau seeding in a Tau biosensor cells. (A) TEM images of Tau, TDP-43-MBP, TDP-43-NTF-MBP and TDP-43-CTF-MBP only (50 µM), and Tau in presence of TDP-43-MBP, TDP-43-NTF-MBP and TDP-43-CTF-MBP at equimolar ratio after 5 days incubation. Scale bars: 0.1 µm for TDP-43-MBP only, TDP-43-NTF-MBP only, TDP-43-CTF-MBP only, and Tau+TDP-43-CTF-MBP; 0.2 µm for Tau+TDP-43-MBP and Tau+TDP-43-NTF-MBP; 0.5 µm for Tau only. (B) Quantification of fibril length (µm) from (n ≥ 2) biological replicates and (n ≥ 5) technical replicates; values show the length of protein structures in µm and the bar graphs represent the mean ± SEM; ****P < 0.0001 by one-way ANOVA with Dunnett´s multiple comparison test to Tau only. (C) Scheme of Tau seeding assay in HEK293 GFP/YFP-TauRDP301S using in vitro generated Tau assemblies as seeds; created with BioRender.com. (D) Representative confocal images of cytosolic Tau aggregates (green) formed after seeding Tau biosensor cells with 5 days old recombinant Tau aggregates +/− TDP-43-MBP, TDP-43-NTF-MBP, TDP-43-CTF-MBP, MBP and α-synuclein. The ‘No seeds’ condition refers to cells treated with lipofectamine only. Scale bar: 70 µm in overview and 20 µm in inset. (E) Quantification of number of aggregates per cell. Bar graphs show the number of biological replicates ± SEM in (n = 5) biological replicates (different batches of cells on different days). *P = 0.0274 by one-way ANOVA Kruskal–Wallis test with Dunn´s multiple comparison test to Tau only condition.CC BY · PubMed Central
Figure EV4 Western blot characterization of SarkoSpin extracts from human patients. (A) anti-Tau antibody; (B) Anti-phospho-TDP-43 (S409/410) antibody; (C) Anti-TDP-43 antibody; (D) Anti-α-synuclein antibody. Western blots of SarkoSpin fractions derived from the frontal cortex of non-ND, AD + , AD–, FTLD-TDP, and FTLD-Tau patients, and from the cingulate cortex of PD patients, probed with the indicated antibodies. Dashed lines indicate divisions within the same blot.
Figure EV4 Western blot characterization of SarkoSpin extracts from human patients. (A) anti-Tau antibody; (B) Anti-phospho-TDP-43 (S409/410) antibody; (C) Anti-TDP-43 antibody; (D) Anti-α-synuclein antibody. Western blots of SarkoSpin fractions derived from the frontal cortex of non-ND, AD + , AD–, FTLD-TDP, and FTLD-Tau patients, and from the cingulate cortex of PD patients, probed with the indicated antibodies. Dashed lines indicate divisions within the same blot.CC BY · PubMed Central
Figure EV5 Characterization of patient-derived SarkoSpin extracts by immunohistochemistry and dual immunofluorescence. (A, B) Immunohistochemical images of representative non-ND and AD+ brain sections stained with antibodies against phosphorylated Tau (AT8) and TDP-43 in either the hippocampus or frontal cortex. Scale bar: 50 μm. (C) Double fluorescence immunostaining of two representative AD+ cases showing phosphorylated Tau (AT8, green) and TDP-43 (red) in the hippocampus. Scale bar: 30 μm.
Figure EV5 Characterization of patient-derived SarkoSpin extracts by immunohistochemistry and dual immunofluorescence. (A, B) Immunohistochemical images of representative non-ND and AD+ brain sections stained with antibodies against phosphorylated Tau (AT8) and TDP-43 in either the hippocampus or frontal cortex. Scale bar: 50 μm. (C) Double fluorescence immunostaining of two representative AD+ cases showing phosphorylated Tau (AT8, green) and TDP-43 (red) in the hippocampus. Scale bar: 30 μm.CC BY · PubMed Central
Figure 7 Sarkospin extracts from AD patients with Tau/TDP-43 co-pathology (AD+) show a lower Tau seeding potency compared to AD patients with Tau-only pathology (AD−) and contain TDP-43 seeding competent species. (A) Scheme of Tau seeding assay in HEK293 GFP/YFP-TauRDP301S using SarkoSpin patient extracts as seeds; created with BioRender.com. (B) Representative confocal images of cytosolic Tau aggregates (green) formed after seeding the cells with non-ND 1, FTLD-Tau 2, AD − 2, AD + 2, FTLD-TDP 5, or PD 2 SarkoSpin extracts. Scale bar: 70 µm in overview and 15 µm in inset. (C) Quantification of number and area of aggregates per cell. Bar graphs show values ± SEM in (n = 4) biological replicates (different batches of cells in different days), and individual dots correspond to different patients. ****P < 0.0001, **P = 0.0030, and *P = 0.0317 (number of aggregates), and ****P < 0.0001, **P = 0.0033, and *P = 0.0173 (area of aggregates) by one-way ANOVA with Šídák´s multiple comparison test to non-ND. (D) Scheme of TDP-43 seeding assay using doxycycline-inducible TDP-43-HA HEK293 cells; created with BioRender.com. (E) Representative confocal images of cytosolic pS409/410-positive TDP-43 neoaggregates in HEK293 cells, after transfection with non-ND 1, FTLD-TDP 5, AD + 2, AD − 2, FTLD-Tau 2, or PD 2 SarkoSpin patient extracts. DAPI is depicted in blue, HA staining in green, and pS409/410 in magenta. Scale bar: 50 µm in overview and 10 µm in inset. (F) Quantification of HA and pS409/410-TDP-43 colocalization as number and area of neoaggregates per cell. Bar graphs show values ± SEM in (n = 4) biological replicates (different batches of cells in different days), and individual dots correspond to different patients. **P = 0.0043 and *P = 0.0207 by one-way ANOVA with Dunnett´s multiple comparison test to non-ND.
Figure 7 Sarkospin extracts from AD patients with Tau/TDP-43 co-pathology (AD+) show a lower Tau seeding potency compared to AD patients with Tau-only pathology (AD−) and contain TDP-43 seeding competent species. (A) Scheme of Tau seeding assay in HEK293 GFP/YFP-TauRDP301S using SarkoSpin patient extracts as seeds; created with BioRender.com. (B) Representative confocal images of cytosolic Tau aggregates (green) formed after seeding the cells with non-ND 1, FTLD-Tau 2, AD − 2, AD + 2, FTLD-TDP 5, or PD 2 SarkoSpin extracts. Scale bar: 70 µm in overview and 15 µm in inset. (C) Quantification of number and area of aggregates per cell. Bar graphs show values ± SEM in (n = 4) biological replicates (different batches of cells in different days), and individual dots correspond to different patients. ****P < 0.0001, **P = 0.0030, and *P = 0.0317 (number of aggregates), and ****P < 0.0001, **P = 0.0033, and *P = 0.0173 (area of aggregates) by one-way ANOVA with Šídák´s multiple comparison test to non-ND. (D) Scheme of TDP-43 seeding assay using doxycycline-inducible TDP-43-HA HEK293 cells; created with BioRender.com. (E) Representative confocal images of cytosolic pS409/410-positive TDP-43 neoaggregates in HEK293 cells, after transfection with non-ND 1, FTLD-TDP 5, AD + 2, AD − 2, FTLD-Tau 2, or PD 2 SarkoSpin patient extracts. DAPI is depicted in blue, HA staining in green, and pS409/410 in magenta. Scale bar: 50 µm in overview and 10 µm in inset. (F) Quantification of HA and pS409/410-TDP-43 colocalization as number and area of neoaggregates per cell. Bar graphs show values ± SEM in (n = 4) biological replicates (different batches of cells in different days), and individual dots correspond to different patients. **P = 0.0043 and *P = 0.0207 by one-way ANOVA with Dunnett´s multiple comparison test to non-ND.CC BY · PubMed Central

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Cited by

Metadata

Authors
Simonetti, F., Zhong, W., Hutten, S., Uliana, F., Schifferer, M., Rezaei, A., Ramirez, L. M., Hochmair, J., Sankar, R., Gopalan, A., Kielisch, F., Riemenschneider, H., Ruf, V., Schmidt, C., Simons, M., Zweckstetter, M., Wegmann, S., Lashley, T., Polymenidou, M., Edbauer, D., & Dormann, D.
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2025-10-17
Volume
44
Issue
24
ISSN
  • 0261-4189
  • 1460-2075
DOI
10.1038/s44318-025-00590-2
PMC
PMC12706024
Cited by
23
References
19
Language
en
Licence
Funders
  • Alzheimers Research Award by the Hans and Isle Breuer Foundation
  • Deutsche Forschungsgemeinschaft (442698351, 390857198, 408885537, 497669232, INST 247/912-1FUGG)
  • Swiss National Science Foundation (310030_192650)
  • Marie Curie Individual Fellowship (101207537)
  • SPP2191 (419138680, 419139133)
  • SFB1551 (464588647)
  • Ministry of Science and Health of Rhineland-Palatinate and the European Regional Development Fund (84012490)
  • Association for Frontotemporal Dementia
  • Bundesministerium für Bildung und Forschung (03Z22HN22)

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.