Templated paired helical filament formation and tau fold-dependent inclusion morphologies in primary neurons
- 1MRC Laboratory of Molecular Biology
Abstract
Neurodegenerative tauopathies are characterized by the abnormal assembly of tau into amyloid filaments with distinct, disease-specific folds. These filaments are proposed to spread in a prion-like manner, thus underlying the progression of pathology in diseased brains. A prediction of this hypothesis is that tau filaments will induce progeny filaments identical to the input seed material, yet cellular models of templated tau assembly have failed to fully recapitulate brain-derived filament structures. Here, we show that mixed primary mouse cortical neurons overexpressing full-length human tau via adeno-associated virus transduction propagate Alzheimer's disease paired helical filaments upon exposure to human brain-derived seeds. Using minimal tags and core mutations, we were able to unambiguously differentiate induced aggregates from the original seeds. Super-resolution microscopy and live-cell imaging revealed progressive inclusion formation in neurons. Moreover, seeding primary neurons with brain extracts from individuals with Pick's disease, corticobasal degeneration and progressive supranuclear palsy induced the formation of morphologically distinct inclusions. Together, these findings establish that primary neurons provide an environment for the faithful propagation of paired helical filaments and show that tau filament folds dictate higher-order inclusion morphologies within neurons.
Related
- Templated seeding induces the formation of Alzheimer paired helical tau filaments in human brain organoids
- Spatiotemporal Analysis of Intranuclear Inclusion Body and Virus Formation in Human Adenovirus Type 5-Infected Cells
- WHIRLY1 Interactome Profiling Reveals the Chloroplast Fate Correlation with Stromule-like Morphologies in Arabidopsis Leaves Under Dark and DBMIB Stress Conditions
- STRIPAK associates with Rabex5-Rabaptin5 to promote Rab5-dependent early endosome formation and EGFR transport
- Species-dependent water and salt migration drives lipoprotein remodeling and quality formation during rapid curing of separated egg yolks.
BibTeX
@misc{huang2026templated,
title = {{Templated paired helical filament formation and tau fold-dependent inclusion morphologies in primary neurons}},
author = {M. Huang and S. Lövestam and K. A. X. Cheam and B. Ghetti and W. A. McEwan and S. H. W. Scheres and M. Goedert},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755038},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755038v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Templated paired helical filament formation and tau fold-dependent inclusion morphologies in primary neurons
AU - M. Huang
AU - S. Lövestam
AU - K. A. X. Cheam
AU - B. Ghetti
AU - W. A. McEwan
AU - S. H. W. Scheres
AU - M. Goedert
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755038
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755038v1
AB - Neurodegenerative tauopathies are characterized by the abnormal assembly of tau into amyloid filaments with distinct, disease-specific folds. These filaments are proposed to spread in a prion-like manner, thus underlying the progression of pathology in diseased brains. A prediction of this hypothesis is that tau filaments will induce progeny filaments identical to the input seed material, yet cellular models of templated tau assembly have failed to fully recapitulate brain-derived filament structures. Here, we show that mixed primary mouse cortical neurons overexpressing full-length human tau via adeno-associated virus transduction propagate Alzheimer's disease paired helical filaments upon exposure to human brain-derived seeds. Using minimal tags and core mutations, we were able to unambiguously differentiate induced aggregates from the original seeds. Super-resolution microscopy and live-cell imaging revealed progressive inclusion formation in neurons. Moreover, seeding primary neurons with brain extracts from individuals with Pick's disease, corticobasal degeneration and progressive supranuclear palsy induced the formation of morphologically distinct inclusions. Together, these findings establish that primary neurons provide an environment for the faithful propagation of paired helical filaments and show that tau filament folds dictate higher-order inclusion morphologies within neurons.
ER -