Sensitive detection and propagation of brain-derived tau assemblies in HEK293-based wild-type tau seeding assays.

Abstract

The assembly of tau into filaments defines tauopathies, a group of neurodegenerative diseases including Alzheimer's disease (AD), Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). The seeded aggregation of tau has been modeled in cell culture using pro-aggregate modifications such as truncation of N- and C-termini and point mutations within the microtubule-binding repeat domain. This limits the applicability of research findings to sporadic disease, where aggregates contain wild-type, full-length tau. We describe a sensitive and specific biosensor assays for brain-derived tau species utilizing wild-type 0N3R and 0N4R tau expressed in HEK293 cells. We further generate a cell line that propagates AD-templated insoluble tau which is hyperphosphorylated at disease-relevant sites and retains a seeding profile similar to AD. We propose these systems as an advance over existing cell-based seeding assays, as they display specificity to the conformation and isoform composition of sporadic human disease.