Thioflavin S Staining and Amyloid Formation Are Unique to Mixed Tauopathies

Tau phosphorylation, aggregation, and toxicity are the main drivers of neurodegeneration in multiple tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau. Although aggregation and amyloid formation are often assumed to be synonymous, the ability of tau aggregates in different diseases to form amyloids in vivo has not been systematically studied. We used the amyloid dye Thioflavin S to look at tau aggregates in mixed tauopathies such as AD and primary age-related tauopathy, as well as pure 3R or 4R tauopathies such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. We found that aggregates of tau protein only form thioflavin-positive amyloids in mixed (3R/4R), but not pure (3R or 4R), tauopathies. Interestingly, neither astrocytic nor neuronal tau pathology was thioflavin-positive in pure tauopathies. As most current positron emission tomography tracers are based on thioflavin derivatives, this suggests that they may be more useful for differential diagnosis than the identification of a general tauopathy. Our findings also suggest that thioflavin staining may have utility as an alternative to traditional antibody staining for distinguishing between tau aggregates in patients with multiple pathologies and that the mechanisms for tau toxicity may differ between different tauopathies.