Cryo-EM structure of pro-aggregant P301L/S320F double-mutant tau filaments formed in mouse brains following peripheral AAV delivery.
5 affiliations
- 1Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan.
- 2Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo , Bunkyo-Ku, Tokyo, 113-0033, Japan.
- 3Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
- 4Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, Aichi, 467-8601, Japan.
- 5Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan. [email protected].
Abstract
Tauopathies are characterized by the accumulation of abnormally phosphorylated tau filaments, with disease-specific folds revealed by cryo-electron microscopy (cryo-EM). Here, we delivered a recombinant human tau carrying the P301L/S320F double mutation into AppNL-G-F/MAPT double knock-in mice using a blood-brain-barrier-permeable AAV (AAV-PHP.eB), enabling rapid induction of tau aggregation in vivo. The mutant tau was systemically administered via retro-orbital injection, providing a minimally invasive approach for widespread neuronal transduction. Phosphorylated tau aggregation, as well as seeding activity, were observed without the need for exogenous seeds. Our cryo-EM analysis resolved a novel filament fold incorporating residues 279-329, in which the P301L and S320F mutations introduced stabilizing interactions that reinforced filament assembly. This conformation was distinct from previously reported folds, including Alzheimer and Pick tau filaments. Moreover, the filaments adopted a more compact architecture than those observed in patient-derived samples or other model mice. This finding demonstrates that P301L/S320F double-mutant tau adopts a structurally unique, highly aggregation-prone fold, and that this system provides a rapid platform for modeling tau filament formation.
Related
- Cryo-EM structure of RegIIIγ filaments reveals the molecular basis of its bactericidal activity
- Multichannel, biomimetic scaffolds improve functional connectivity following traumatic long-gap peripheral nerve injury.
- Hippocampal extracellular matrix remodeling and temporally distinct glial reorganization following peripheral injury
- Single-cell RNA sequencing delineates compositional and transcriptional changes of porcine peripheral blood mononuclear cell populations following Salmonella I 4,[5],12:i:- inoculation
- Human-Derived Motor Neuron Progenitor Cell Implantation Rescues Motor Endplates Following Peripheral Nerve Injury.
BibTeX
@article{kano2026cryoem,
title = {{Cryo-EM structure of pro-aggregant P301L/S320F double-mutant tau filaments formed in mouse brains following peripheral AAV delivery.}},
author = {Maria Kano and Taeko Kimura and Haruaki Yanagisawa and Komei Yamashita and Lisa Tatsumi and Asahi Sakai and Xinyi Li and Takaomi C Saido and Takashi Saito and Sho Takatori and Masahide Kikkawa and Taisuke Tomita},
journal = {Acta neuropathologica communications},
year = {2026},
month = aug,
doi = {10.1186/s40478-026-02407-7},
url = {https://europepmc.org/article/MED/43010103},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Cryo-EM structure of pro-aggregant P301L/S320F double-mutant tau filaments formed in mouse brains following peripheral AAV delivery.
AU - Maria Kano
AU - Taeko Kimura
AU - Haruaki Yanagisawa
AU - Komei Yamashita
AU - Lisa Tatsumi
AU - Asahi Sakai
AU - Xinyi Li
AU - Takaomi C Saido
AU - Takashi Saito
AU - Sho Takatori
AU - Masahide Kikkawa
AU - Taisuke Tomita
PY - 2026
DA - 2026/08/13
JO - Acta neuropathologica communications
DO - 10.1186/s40478-026-02407-7
UR - https://europepmc.org/article/MED/43010103
AB - Tauopathies are characterized by the accumulation of abnormally phosphorylated tau filaments, with disease-specific folds revealed by cryo-electron microscopy (cryo-EM). Here, we delivered a recombinant human tau carrying the P301L/S320F double mutation into AppNL-G-F/MAPT double knock-in mice using a blood-brain-barrier-permeable AAV (AAV-PHP.eB), enabling rapid induction of tau aggregation in vivo. The mutant tau was systemically administered via retro-orbital injection, providing a minimally invasive approach for widespread neuronal transduction. Phosphorylated tau aggregation, as well as seeding activity, were observed without the need for exogenous seeds. Our cryo-EM analysis resolved a novel filament fold incorporating residues 279-329, in which the P301L and S320F mutations introduced stabilizing interactions that reinforced filament assembly. This conformation was distinct from previously reported folds, including Alzheimer and Pick tau filaments. Moreover, the filaments adopted a more compact architecture than those observed in patient-derived samples or other model mice. This finding demonstrates that P301L/S320F double-mutant tau adopts a structurally unique, highly aggregation-prone fold, and that this system provides a rapid platform for modeling tau filament formation.
SN - 2051-5960
ER -