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Updated: Feb 1, 2026
In Vitro Assay for Studying the Aggregation of Tau Protein and Drug Screening
Published on: November 20, 2018
Tau monomer encodes strains
Apurwa M Sharma1,2, Talitha L Thomas1, DaNae R Woodard1
1Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States.
Abstract:
Tauopathies have diverse presentation, progression, and neuropathology. They are linked to tau prion strains, self-replicating assemblies of unique quaternary conformation, whose origin is unknown. Strains can be propagated indefinitely in cultured cells, and induce unique patterns of transmissible neuropathology upon inoculation into mice. DS9 and DS10 cell lines propagate different synthetic strains that derive from recombinant tau. We previously observed that tau monomer adopts two conformational states: one that is inert (Mi) and one that is seed-competent (Ms) (Mirbaha et al., 2018). We have now found that Ms itself is comprised of multiple stable ensembles that encode unique strains. DS9 monomer inoculated into naive cells encoded only DS9, whereas DS10 monomer encoded multiple sub-strains. Sub-strains each induced distinct pathology upon inoculation into a tauopathy mouse model (PS19). Ms purified from an Alzeimer's disease brain encoded a single strain. Conversely, Ms from a corticobasal degeneration brain encoded three sub-strains, in which monomer from any one re-established all three upon inoculation into cells. Seed competent tau monomer thus adopts multiple, stable seed-competent conformations, each of which encodes a limited number of strains. This provides insight into the emergence of distinct tauopathies, and may improve diagnosis and therapy.
Insights
Seed-competent tau monomer adopts multiple stable conformations, each encoding unique tau prion strains. This finding offers insights into diverse tauopathies and may aid diagnosis and therapy.
Area of Science:
- Neuroscience
- Biochemistry
- Prion Biology
Background:
- Tauopathies exhibit varied clinical and pathological features, linked to distinct tau prion strains.
- The origin of these tau prion strains remains unknown.
- Previous work identified inert (Mi) and seed-competent (Ms) tau monomer conformational states.
Purpose of the Study:
- To investigate the conformational diversity of seed-competent tau monomer.
- To determine if different tau monomer ensembles encode distinct tau prion strains.
- To explore the relationship between tau monomer conformation and tauopathy pathology.
Main Methods:
- Propagation of synthetic tau strains (DS9, DS10) in cell lines.
- Inoculation of tau monomer ensembles into naive cells and tauopathy mouse models (PS19).
- Purification and analysis of seed-competent tau monomer from Alzheimer's disease and corticobasal degeneration brains.
Main Results:
- DS9 monomer propagated a single strain, while DS10 monomer yielded multiple sub-strains.
- Each sub-strain induced distinct neuropathology in PS19 mice.
- Tau monomer from Alzheimer's disease brain encoded one strain, whereas corticobasal degeneration brain yielded three sub-strains.
- Re-establishing all sub-strains from individual components demonstrated their stable, encoding nature.
Conclusions:
- Seed-competent tau monomer exists in multiple stable conformations, each encoding specific tau prion strains.
- This conformational plasticity explains the emergence of diverse tauopathies.
- Findings may inform improved diagnostic and therapeutic strategies for tauopathies.
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