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Updated: Sep 6, 2025
An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Seed-competent tau monomer initiates pathology in a tauopathy mouse model
Hilda Mirbaha1, Dailu Chen2, Vishruth Mullapudi2
1Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract:
Tau aggregation into ordered assemblies causes neurodegenerative tauopathies. We previously reported that tau monomer exists in either inert (Mi) or seed-competent (Ms) conformational ensembles and that Ms encodes strains, that is, unique, self-replicating, biologically active assemblies. It is unknown if disease begins with Ms formation followed by fibril assembly or if Ms derives from fibrils and is therefore an epiphenomenon. Here, we studied a tauopathy mouse model (PS19) that expresses full-length mutant human (1N4R) tau (P301S). Insoluble tau seeding activity appeared at 2 months of age and insoluble tau protein assemblies by immunoblot at 3 months. Tau monomer from mice aged 1 to 6 weeks, purified using size-exclusion chromatography, contained soluble seeding activity at 4 weeks, before insoluble material or larger assemblies were observed, with assemblies ranging from n = 1 to 3 tau units. By 5 to 6 weeks, large soluble assemblies had formed. This indicated that the first detectable pathological forms of tau were in fact Ms. We next examined posttranslational modifications of tau monomer from 1 to 6 weeks. We detected no phosphorylation unique to Ms in PS19 or human Alzheimer's disease brains. We conclude that tauopathy begins with formation of the Ms monomer, whose activity is phosphorylation independent. Ms then self assembles to form oligomers before it forms insoluble fibrils. The conversion of tau monomer from Mi to Ms thus constitutes the first detectable step in the initiation of tauopathy in this mouse model, with obvious implications for the origins of tauopathy in humans.
Insights
The initial step in tauopathies is the formation of seed-competent tau monomers (Ms), not from fibrils, but as an independent event. This phosphorylation-independent process precedes the formation of larger tau aggregates and oligomers, initiating disease progression.
Area of Science:
- Neurodegenerative diseases
- Protein misfolding and aggregation
- Molecular neuroscience
Background:
- Tau aggregation into ordered assemblies is a hallmark of neurodegenerative tauopathies.
- Tau monomer exists in inert (Mi) and seed-competent (Ms) forms, with Ms encoding disease strains.
- The precise initiation event in tauopathy—whether Ms formation precedes fibril assembly or vice versa—remains unclear.
Purpose of the Study:
- To determine the initial event in tauopathy pathogenesis: Ms formation or fibril assembly.
- To investigate the role of posttranslational modifications, specifically phosphorylation, in Ms formation.
- To elucidate the sequence of tau assembly from monomer to insoluble fibrils in a disease model.
Main Methods:
- Utilized the PS19 mouse model expressing mutant human tau (1N4R, P301S).
- Purified tau monomer using size-exclusion chromatography from mice aged 1 to 6 weeks.
- Assessed tau seeding activity, insoluble tau assemblies via immunoblot, and posttranslational modifications.
Main Results:
- Soluble tau seeding activity (Ms) was detected at 4 weeks of age, preceding insoluble tau assemblies (3 months) and seeding activity (2 months).
- Early tau assemblies (n=1-3 units) and larger soluble assemblies were observed by 5-6 weeks.
- No unique phosphorylation patterns were identified in Ms from PS19 mice or human Alzheimer's disease brains.
Conclusions:
- Tauopathy initiates with the formation of the seed-competent tau monomer (Ms), independent of phosphorylation.
- Ms monomers self-assemble into oligomers, subsequently forming insoluble fibrils, establishing the disease cascade.
- The conversion of Mi to Ms represents the earliest detectable step in tauopathy initiation.
