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.