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Updated: Aug 8, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Thioflavin S Staining and Amyloid Formation Are Unique to Mixed Tauopathies
Kimberly L Fiock1,2,3, Ryan K Betters1,4,3, Marco M Hefti1,2,3
1Department of Pathology, University of Iowa, Iowa City, Iowa.
Abstract:
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.
Insights
Tau protein aggregates form amyloid structures only in mixed tauopathies, not pure ones. This finding impacts diagnostic tools for neurodegenerative diseases like Alzheimer's disease.
Area of Science:
- Neuroscience
- Pathology
- Biochemistry
Background:
- Tau phosphorylation, aggregation, and toxicity drive neurodegeneration in tauopathies.
- Alzheimer's disease (AD) and frontotemporal lobar degeneration are key examples.
- The relationship between tau aggregation and amyloid formation in vivo is not fully understood.
Purpose of the Study:
- To systematically investigate if tau aggregates form amyloids in vivo across different tauopathies.
- To compare amyloid formation in mixed (3R/4R) versus pure (3R or 4R) tauopathies.
- To assess the diagnostic utility of thioflavin staining for tau pathologies.
Main Methods:
- Utilized the amyloid dye Thioflavin S.
- Examined tau aggregates in various tauopathies: AD, primary age-related tauopathy, Pick's disease, progressive supranuclear palsy, and corticobasal degeneration.
- Differentiated between mixed (3R/4R) and pure (3R or 4R) tauopathies.
Main Results:
- Tau protein aggregates formed thioflavin-positive amyloids exclusively in mixed (3R/4R) tauopathies.
- No thioflavin-positive tau pathology was observed in pure (3R or 4R) tauopathies, including astrocytic and neuronal forms.
- Thioflavin staining differentiated tau aggregates based on tau isoform composition.
Conclusions:
- Tau aggregates form amyloids in vivo only in mixed tauopathies, not pure tauopathies.
- Current positron emission tomography tracers, based on thioflavin derivatives, may be better suited for differential diagnosis than general tauopathy identification.
- Thioflavin staining offers potential as an alternative to antibody staining for distinguishing tau aggregates in complex pathologies and suggests differing toxicity mechanisms.
