Distinct recombinant tau fibril conformations induce divergent propagation and neurodegenerative phenotypes in a model mouse

Intracellular tau aggregation is a central pathological feature of tauopathies, including Alzheimer’s disease (AD), yet the relationships among distinct tau aggregate species, pathological propagation, and neurotoxicity remain incompletely understood. In particular, it is unclear whether structural differences among tau fibrils determine the downstream pathological heterogeneity, such as inflammatory responses and neurodegeneration in vivo. Here, we established a seed-dependent tau propagation model using a tauopathy mouse model that overexpresses mutant human tau (P301L) and develops age-dependent tau pathology without early intrinsic aggregation, enabling clear discrimination of inoculum-driven effects. We generated two structurally distinct recombinant tau preformed fibrils (PFFs): polymorphic P301L-K18 (K18 P301L; Q244-E372 tau fragment with P301L mutation) fibrils and structurally homogeneous 0N3R G3 (G3 WT; 0N3R tau amplified by I297-E391 tau fibrils as seeds) fibrils that resemble AD paired helical filaments. Following unilateral hippocampal inoculation, both PFFs induced robust AT8-positive phosphorylated tau deposition at the injection site; however, their pathological profiles diverged substantially. K18 P301L PFFs promoted widespread propagation of tau aggregates to anatomically connected regions, accompanied by microglial activation, reduced P2RY12 expression, and thinning of the CA1 pyramidal cell layer. In contrast, G3 WT PFFs induced dense intraneuronal tau accumulation at the injection site with limited propagation and comparatively mild neuroinflammation. Notably, G3 WT PFFs induced abundant β-sheet-rich tau structures at the injection site, yet elicited only limited neuroinflammation and neurodegeneration, suggesting that aggregate-associated properties, rather than aggregate burden alone, may contribute to downstream pathological outcomes. Our study demonstrates that distinct recombinant tau PFF preparations can induce divergent pathological phenotypes in vivo and provides an experimental platform for investigating how aggregate-associated properties influence tau propagation, neuroinflammation, and neurodegeneration.