Basic Science and Pathogenesis | JoVE Visualize

Area of Science:

Neuroscience
Biochemistry
Structural Biology

Background:

Tau protein is a key component of paired helical filaments (PHFs) in Alzheimer's disease.
Over thirty neurodegenerative diseases feature filamentous tau inclusions, with mutations in the tau gene linked to frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
Transgenic mouse models exhibiting tau inclusions and neurodegeneration have been developed, demonstrating tau's prion-like properties.

Purpose of the Study:

To determine the near-atomic structures of tau filaments from human brains using electron cryo-microscopy (cryo-EM).
To elucidate the distinct molecular conformers and folds of assembled tau in various tauopathies.
To investigate the potential for in vitro refolding of human tau disease folds for mechanistic studies.

Main Methods:

Electron cryo-microscopy (cryo-EM) was employed to determine the structures of tau filaments.
Analysis of tau filament structures from human brains affected by Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy (CTE), corticobasal degeneration, argyrophilic grain disease, progressive supranuclear palsy, globular glial tauopathy, and limbic-predominant neuronal inclusion body four-repeat tauopathy.
In vitro assembly of truncated or modified full-length human tau to replicate disease-associated folds.

Main Results:

Distinct tau folds were identified for Alzheimer's disease and Pick's disease, confirming molecular conformers of assembled tau.
Tau filaments from CTE brains, while containing all six tau isoforms, exhibit a distinct fold compared to Alzheimer's disease.
Sporadic four-repeat tauopathies were classified based on their four-layered (corticobasal degeneration, argyrophilic grain disease) or three-layered (progressive supranuclear palsy, globular glial tauopathy) structures, enabling identification of new disease entities like limbic-predominant neuronal inclusion body four-repeat tauopathy.

Conclusions:

Each sporadic tauopathy possesses a unique tau fold, though some folds may be shared across different diseases.
Replicating human disease tau folds in vitro is crucial for studying disease mechanisms.
Current in vitro assembled tau filament structures differ from those found in the human brain; however, the Alzheimer's fold has been successfully formed in vitro using modified tau.