Small tau aggregates exhibit disease-specific molecular profiles across tauopathies

Böken, D.; Huang, M.; Wu, Y.; Fertan, E.; Lam, J. Y. L.; Meisl, G.; Baig, S.; Rowe, J.; Smith, C.; Quaegebeur, A.; Cox, D.; McEwan, W. A.; Klenerman, D.

doi:10.1101/2025.06.10.658934

bioRxiv · 10.1101/2025.06.10.658934

Small tau aggregates exhibit disease-specific molecular profiles across tauopathies

Böken, D.·Huang, M.·Wu, Y.·Fertan, E.·Lam, J. Y. L.·Meisl, G.·Baig, S.·Rowe, J.·Smith, C.·Quaegebeur, A.·Cox, D.·McEwan, W. A.·Klenerman, D.

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Abstract

Tauopathies are neurodegenerative diseases marked by pathological tau aggregation. While disease-specific folds of insoluble tau filaments have been established, it remains unclear whether the smaller, earlier species also differ across tauopathies. Here, we characterise these small tau aggregates from post-mortem brain of individuals with Alzheimers disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration, Picks disease, and healthy controls. Using two complementary single-molecule assays, we confirm that small tau aggregates vary in abundance, morphology, and post-translational modifications. AD features specific long, fibrillar-shaped aggregates enriched in phospho-epitopes, while PSP aggregates are shorter, round, and selectively phosphorylated at serine-356, a site we identify as correlating with markers of inflammation and apoptosis. Aggregate properties co-vary with cellular stress signatures and align with disease-specific seeding profiles, suggesting distinct pathological mechanisms. These findings suggest that small tau aggregates are not a shared intermediate, but instead encode disease-specific mechanisms, with potential as both biomarkers and therapeutic targets. Key pointsSmall tau aggregates show disease-specific signatures across tauopathies, differing in abundance, morphology, and post-translational modifications. Tau aggregates in AD show enhanced phosphorylation density and structural heterogeneity, including a distinct population of long fibrillar species detectable in the soluble fraction. Alzheimers disease is characterised by specific long, fibrillar-shaped tau aggregates enriched in disease-relevant phospho-epitopes. PSP features round pSer356-positive aggregates that correlate with apoptotic and inflammatory markers, suggesting a distinct mechanism of toxicity. Isoform-specific biosensor assays reveal divergent seeding behaviour: CBD shows strong 4R seeding, while PSP lacks seeding activity. Features of small aggregates co-vary with distinct patterns of gliosis and cell stress, suggesting disease-specific mechanisms of tau-mediated toxicity.

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Böken, D., Huang, M., Wu, Y., Fertan, E., Lam, J. Y. L., Meisl, G., Baig, S., Rowe, J., Smith, C., Quaegebeur, A., Cox, D., McEwan, W. A., Klenerman, D.. 2025-06-11. Small tau aggregates exhibit disease-specific molecular profiles across tauopathies. https://doi.org/10.1101/2025.06.10.658934

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