Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency

Alysa Kasen, Sofia Lövestam, Libby Breton, Lindsay Meyerdirk, Jacob Alec McPhail, Kristin Piche, Ariel Louwrier, Colt D. Capan, Hyoungjoo Lee, Sjors H. W. Scheres and Michael X. Henderson ()
Additional contact information
Alysa Kasen: Van Andel Institute
Sofia Lövestam: MRC Laboratory of Molecular Biology
Libby Breton: Van Andel Institute
Lindsay Meyerdirk: Van Andel Institute
Jacob Alec McPhail: StressMarq Biosciences Inc.
Kristin Piche: StressMarq Biosciences Inc.
Ariel Louwrier: StressMarq Biosciences Inc.
Colt D. Capan: Van Andel Institute
Hyoungjoo Lee: Van Andel Institute
Sjors H. W. Scheres: MRC Laboratory of Molecular Biology
Michael X. Henderson: Van Andel Institute

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Tau misfolding into β-sheet–rich filaments and subsequent recruitment of monomeric tau are central to Alzheimer’s disease (AD) pathogenesis. While cryo-EM has resolved the conformation of the AD tau core, the structural features conferring biological activity remain unclear. Here, we investigated how tau filament core structure and post-translational modifications influence seeding capacity in neurons and mice. Our findings show that although filament structure impacts seeding, the AD tau core alone is insufficient to fully replicate AD tau’s biological activity. The unstructured fuzzy coat, particularly phosphorylation within this region, is essential for full seeding competence. Importantly, recombinant tau filaments bearing twelve phospho-mimetic residues (PAD12 tau) and adopting the AD fold recapitulate the seeding activity of native AD tau. These results demonstrate that tau filament pathogenicity arises from the combined contributions of both the ordered core structure and post-translational modifications within the fuzzy coat, providing critical insights into mechanisms underlying tau-driven neurodegeneration.

Date: 2025
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DOI: 10.1038/s41467-025-64312-2

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