Abstract

The accumulation of hyperphosphorylated, aggregated tau in neurons is one of the hallmarks of Alzheimer’s disease (AD). Recent work in structural biology has solved the structure of tau fibrils in several tauopathies and found that the structure of the tau fibrils varies between diseases. Still, fibril structure is conserved among patients within the same disease, suggesting that tau fibril structure relates to its pathogenicity. Tau fibrils derived from AD brain (AD PHF) seed AD-like pathology in wild-type (WT) mice, yet efforts to recapitulate this seeding with recombinant fibrils have failed. We hypothesized that recombinant fibrils that recapitulate the core region structure of AD tau will show similar seeding capacity to AD tau, with PTMs playing a modulatory role.
We screened recently developed recombinant tau fibrils with diverse structures to investigate how tau fibril structure and PTMs are related to tau seeding capacity in primary cortical neurons. Fibrils of interest from the initial screen were then assessed through hippocampal injection into WT and MAPT KI mice.
The screening method showed that fibrils resembling the core structure of an AD PHF had a higher seeding capacity than other fibrils. We also found that full-length recombinant tau fibrils containing PTMs had a higher seeding capacity than packed length fibrils without PTMs. However, the replication of the core structure in truncated fibrils and the presence of PTMs alone are insufficient to fully replicate the seeding capacity of AD PHFs. Our finding of altered seeding capacity due to fibril structure in the seeding model was replicated in WT and MAPT KI mice.
The structure and PTM patterns of tau fibrils appear to be closely tied to fibril pathogenicity, with recombinant fibrils more closely resembling AD PHFs having a more similar seeding capacity. We believe that generating fibrils that more closely resemble AD PHFs can lead to improved model systems of tau pathology in AD.