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Updated: Apr 29, 2026
An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Distinct tau prion strains propagate in cells and mice and define different tauopathies
David W Sanders1, Sarah K Kaufman1, Sarah L DeVos1
1Department of Neurology, Washington University in St. Louis, St. Louis, MO 63105, USA.
Abstract:
Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations ("strains") in vivo that link structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy.
Insights
Tau protein aggregates propagate like prions, forming distinct strains that cause specific neurodegenerative tauopathies. This prion-like behavior explains disease diversity and may aid diagnosis and therapy.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Neurodegenerative tauopathies exhibit stereotyped progression, potentially driven by prion-like tau aggregation.
- True prions are defined by their ability to stably maintain unique conformations (strains) that correlate with specific pathologies.
Purpose of the Study:
- To determine if tau protein exhibits prion-like characteristics, including the stable propagation of distinct conformations (strains).
- To investigate the link between tau strains and the phenotypic diversity observed in various tauopathies.
Main Methods:
- Cultured cells were used to propagate stable tau conformations (strains) from the tau repeat domain.
- In vitro-generated tau strains were inoculated into transgenic mice over successive generations to assess in vivo pathology.
- Tau was immunopurified from affected mice to confirm strain propagation in culture.
- Tau strains were isolated from patient-derived samples of five different tauopathies.
Main Results:
- The tau repeat domain propagated distinct amyloid conformations clonally and indefinitely in culture.
- Reintroduction of tau from these cell lines into naive cells recreated identical clones.
- Two distinct tau strains produced different pathologies in vivo across three generations of mice.
- Immunopurified tau from mice recapitulated the original in vitro strains.
- Distinct sets of tau strains were associated with different tauopathy diseases in patients.
Conclusions:
- Tau protein exhibits essential characteristics of a prion, including the stable propagation of distinct strains.
- The prion-like behavior of tau may explain the phenotypic diversity of tauopathies.
- Identification of tau strains could lead to improved diagnostic and therapeutic strategies for tauopathies.
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