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TitleSerial amplification of tau filaments using Alzheimer's brain homogenates and C322A or C322S recombinant tau.
Journal, issue, pagesFEBS Lett, Vol. 599, Issue 19, Page 2768-2778, Year 2025
Publish dateSep 30, 2025
AuthorsAlessia Santambrogio / Sofia Lövestam / Michael A Metrick / Thomas Löhr / Peifeng Xu / Nicholas C T Gallagher / Bernardino Ghetti / Byron Caughey / Sjors H W Scheres / Michele Vendruscolo /
PubMed AbstractThe assembly of tau into amyloid filaments is a hallmark of Alzheimer's disease (AD) and other tauopathies. Cryo-EM revealed the existence of disease-specific tau folds, which are challenging to ...The assembly of tau into amyloid filaments is a hallmark of Alzheimer's disease (AD) and other tauopathies. Cryo-EM revealed the existence of disease-specific tau folds, which are challenging to replicate in vitro. We studied three full-length recombinant 0N3R tau forms (the wild-type and the C322A and C322S variants) using an RT-QuIC assay with brain homogenate seeding. C322A tau formed filaments resembling AD paired helical filaments (PHFs) but with a more open C-shaped core. C322S tau yielded structurally distinct filaments with an ordered C-terminal region. Both mutants seeded further aggregation, whereas the wild-type showed poor reproducibility and mainly unfolded aggregates. These results highlight the importance of optimised conditions to produce disease-relevant tau filaments and aid the development of targeted therapies. Impact statement We investigated the seeded assembly of 0N3R tau and its two mutational variants C322A and C322S, using Alzheimer's disease brain homogenates in a real-time quaking-induced conversion (RT-QuIC) assay. The C322A variant formed filaments partially resembling the AD PHF structure, showing the importance of optimised conditions to produce disease-relevant tau filaments.
External linksFEBS Lett / PubMed:41026859 / PubMed Central
MethodsEM (helical sym.)
Resolution2.6 - 2.8 Å
Structure data

EMDB-53527, PDB-9r2f:
Tau filaments seeded by AD homogenate using 0N3R C322A
Method: EM (helical sym.) / Resolution: 2.8 Å

EMDB-53530, PDB-9r2h:
Tau filaments seeded by AD homogenate using 0N3R C322S
Method: EM (helical sym.) / Resolution: 2.6 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / MAPT / Tau / Alzheimer's Disease / RT-QuiC

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