Templated paired helical filament formation and tau fold-dependent inclusion morphologies in primary neurons

Neurodegenerative tauopathies are characterized by the abnormal assembly of tau into amyloid filaments with distinct, disease-specific folds. These filaments are proposed to spread in a prion-like manner, thus underlying the progression of pathology in diseased brains. A prediction of this hypothesis is that tau filaments will induce progeny filaments identical to the input seed material, yet cellular models of templated tau assembly have failed to fully recapitulate brain-derived filament structures. Here, we show that mixed primary mouse cortical neurons overexpressing full-length human tau via adeno-associated virus transduction propagate Alzheimer's disease paired helical filaments upon exposure to human brain-derived seeds. Using minimal tags and core mutations, we were able to unambiguously differentiate induced aggregates from the original seeds. Super-resolution microscopy and live-cell imaging revealed progressive inclusion formation in neurons. Moreover, seeding primary neurons with brain extracts from individuals with Pick's disease, corticobasal degeneration and progressive supranuclear palsy induced the formation of morphologically distinct inclusions. Together, these findings establish that primary neurons provide an environment for the faithful propagation of paired helical filaments and show that tau filament folds dictate higher-order inclusion morphologies within neurons.

Neurodegenerative tauopathies are characterized by the assembly of tau protein into disease-specific amyloid folds. While prion-like propagation is hypothesized to drive disease progression, cell models have previously failed to fully replicate human-brain derived filament structures. Here we show that primary mouse neurons support the templated propagation of human Alzheimer's disease paired helical filaments. By incorporating a disease-causing mutation (V337M) into the amyloid core, we unambiguously resolved cryo-EM structures of the induced assemblies. Moreover, by using super-resolution light microscopy, we show that seeds from tauopathies induced the formation of morphologically distinct intraneuronal inclusions. These findings describe a system for dissecting the cellular factors that govern tau fold propagation and for understanding how distinct filament structures dictate phenotypic differences across tauopathies.