Modeling tauopathy using human-like pathogenic tau seeds.

Abstract

Compared with traditional transgenic models of tauopathy, there is no confounding effect from the insertion of the exogenous gene and overexpression of the human mutant tau in the tau spreading models. By strategically choosing the location and time of the inoculation, we can spatiotemporally determine the starting point of tau pathology in the model mimicking the development of tauopathy. Moreover, they recapitulate the strain-specific features of tau pathology. Regardless of these advantages, human-like tau spreading models are very much confined due to the limitation on quantity and quality of tau seeds. In vitro seeding assay has shown its great potential of amplifying the pathogenic tau seeds to expand their quantity and increase their quality. In the study, we used biochemically enriched, human-derived, tau aggregates as seeds to template recombinant tau (rT40) in vitro. Using biochemistry and electron microscopy, we examined the biophysical properties of the amplified materials and the human-derived tau seeds. We also interrogated the pathogenicity of the amplified human-like tau strains with orthogonal spreading models of tauopathy. As a result, we observed elongated tau filaments with recombinant T40 attached to the seeds. Compared with the seeds control, the amplified tau strains showed increased pathogenic tau species after seeding. The amplified tau strains recapitulate the pathogenicity and biophysical property of the original seeds. Our data suggest that the in vitro seeded recombinant tau can be recruited onto the seeds and converted into the confirmation of pathological tau seeds in a strain-dependent manner. Along with the conversion, the pathogenicity of different tau strains can be conferred and conserved into the recombinant tau. The study provides an authentic way of amplifying tau strains in vitro as well as a tool to expand our ability to understand tau fibrillization and transmission.