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

Authors

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.

Abstract

Tau aggregation at synapses is a key process driving Alzheimer's 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 TNFa. Using aggregate-specific SIMOA, STED microscopy, and SynPull to detect nanoscopic tau aggregates in bulk samples and at individual synapses, we found that TNFa-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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Jun 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.