Tau aggregate replication occurs at the pre-synapse of cultured human neurons and increases with application of TNFa

Kedia, S.; Fertan, E.; Paul, A.; Davi, V.; Nolan, G.; Baranes, K.; Wu, Y.; Kim, J. E.; Quaegebeur, A.; Kotter, M. R. N.; Avezov, E.; Meisl, G.; Klenerman, D.

doi:10.64898/2026.05.30.728997

bioRxiv · 10.64898/2026.05.30.728997

Tau aggregate replication occurs at the pre-synapse of cultured human neurons and increases with application of TNFa

Kedia, S.·Fertan, E.·Paul, A.·Davi, V.·Nolan, G.·Baranes, K.·Wu, Y.·Kim, J. E.·Quaegebeur, A.·Kotter, M. R. N.·Avezov, E.·Meisl, G.·Klenerman, D.

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Abstract

Tau aggregation at synapses is a key process driving Alzheimers disease but the mechanism(s) that cause this have not been established. We used a model system of forward-programming induced glutamatergic neurons (iNeurons) with three independent cell lines treated with TNF[a]. Using aggregate-specific SIMOA, STED microscopy, and SynPull to detect nanoscopic tau aggregates in bulk samples and at individual synapses, we found that TNF[a]-driven tau aggregation occurs preferentially at the pre-synapse, forming predominantly non-fibrillar aggregates that are larger than ones in the extra- and post-synaptic regions. Using mathematical models of aggregate formation, we fitted the frequency of AT8-positive tau aggregates in synaptosomes, which showed that aggregate replication is the dominant process and is much faster than de-novo aggregate formation, leading to rapid local amplification once one aggregate is formed. Our results provide direct evidence for tau aggregate replication at the pre-synapse, linking inflammation induced tau aggregation with synaptic pathology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/728997v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@169dacorg.highwire.dtl.DTLVardef@c9894corg.highwire.dtl.DTLVardef@1551253org.highwire.dtl.DTLVardef@260ae7_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kedia, S., Fertan, E., Paul, A., Davi, V., Nolan, G., Baranes, K., Wu, Y., Kim, J. E., Quaegebeur, A., Kotter, M. R. N., Avezov, E., Meisl, G., Klenerman, D.. 2026-06-03. Tau aggregate replication occurs at the pre-synapse of cultured human neurons and increases with application of TNFa. https://doi.org/10.64898/2026.05.30.728997

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