Journal Article

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

Kasen, Alysa, Breton, Libby, Meyerdirk, Lindsay, Louwrier, Ariel, Capan, Colt D., Piche, Kristin, Lee, Hyoungjoo, Scheres, Sjors H. W., Henderson, Michael X., Lövestam, Sofia, McPhail, Jacob Alec

2025

Overview

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. Tau misfolds in Alzheimer’s disease, but how the link between tau filament structure and pathogenicity is unclear. This study shows that both filament core structure and phosphorylation in the fuzzy coat are required for full seeding capacity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 101/58 / 13/106 / 631/378/1689/1283 / 631/535/1258/1259 / 64 / 64/60 / 82/51 / 82/83 / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Animals / Biological activity / Brain / Cell death / Conformation / Dementia / Disease / Filaments / Humanities and Social Sciences / Humans / Mice / multidisciplinary / Neurodegenerative diseases / Neurons / Neurons - metabolism / Pathogenesis / Pathogenicity / Pathogens / Pathology / Phosphorylation / Post-translation / Protein Folding / Protein Processing, Post-Translational / Protein seeding / Proteins / Science / Science (multidisciplinary) / Seeds / Tau protein / tau Proteins - chemistry / tau Proteins - genetics / tau Proteins - metabolism / Tissues / Translation