The term "tau strains" refers to structurally distinct conformations of aggregated tau protein that characterize different neurodegenerative diseases. Cryo-electron microscopy (cryo-EM) has revolutionized our understanding of tauopathies by revealing the unique three-dimensional folds of tau filaments in each disease. Unlike the uniform paired helical filaments seen in Alzheimer's disease, the 4R-tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, and FTDP-17) each exhibit distinct tau filament structures that correlate with their clinical phenotypes[1].
The tau strain hypothesis proposes that different conformations of aggregated tau ("strains") encode disease-specific information, similar to prions. These strains:
Cryo-EM allows visualization of tau filaments at near-atomic resolution, revealing:
The field was transformed by the work of Fitzpatrick et al. (2017) who solved the structure of tau filaments from Alzheimer's disease brain, followed by similar studies on PSP, CBD, AGD, and other tauopathies[3].
Filament Type: Straight tau filaments (STF), not paired helical filaments
Structural Features:
Pathological Context: PSP shows predominant involvement of the basal ganglia, brainstem, and cerebellar nuclei, with neurofibrillary tangles made of 4R tau in neurons and tufted astrocytes.
Filament Type: Mixed morphology including both straight and twisted filaments
Structural Features:
Pathological Context: CBD shows 4R tau in neurons, astrocytes (including astrocytic plaques), and oligodendrocytes (coiled bodies).
Filament Type: Short, argyrophilic grains composed of 4R tau
Structural Features:
Pathological Context: AGD shows argyrophilic grains (hence the name), which are silver-positive, spindle-shaped tau inclusions primarily in the limbic system.
Filament Type: Globular tau inclusions in glial cells
Structural Features:
Pathological Context: GGT shows prominent 4R tau in oligodendrocytes forming globular inclusions, with lesser neuronal involvement.
Filament Type: Variable depending on the specific mutation
Structural Features:
Pathological Context: FTDP-17 shows variable pathology depending on the specific mutation, with some cases resembling PSP and others showing distinct patterns.
| Disease | Primary Filament | Protofilaments | Core Structure | Key Distinguishing Feature |
|---|---|---|---|---|
| PSP | Straight filaments | 2 | C-shaped pair | Astrocytic tufts |
| CBD | Mixed (straight/twisted) | 2 | C-shaped pair | Astrocytic plaques |
| AGD | Short argyrophilic grains | 2 | C-shaped pair | Small grain lesions |
| GGT | Globular glial inclusions | 2 | C-shaped pair | Oligodendrocyte globules |
| FTDP-17 | Variable | 1-2 | Mutation-dependent | Mutation-specific |
The distinct structural features of different tau strains have important therapeutic implications:
Several anti-tau therapies are in development, with some specifically targeting 4R-tauopathies:
All 4R-tauopathies share:
Each disease has unique:
Recent studies have further refined our understanding of tau strain structures:
New findings on how tau strains propagate in 4R tauopathies:
Strain-specific biomarkers are emerging:
Fitzpatrick et al. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017. ↩︎
Goedert et al. Tau prion strains and neurodegenerative disease. Trends in Cell Biology. 2017. ↩︎
Fitzpatrick et al. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017. ↩︎
Flasch et al. Cryo-EM structures of tau filaments from progressive supranuclear palsy. Nature. 2020. ↩︎
Arakham et al. Cryo-EM structure of corticobasal degeneration tau filaments. Acta Neuropathologica. 2022. ↩︎
Shi et al. Cryo-EM structures of tau filaments from argyrophilic grain disease. Acta Neuropathologica. 2021. ↩︎
Kovacs et al. 'Globular glial tauopathy: A novel 4R tauopathy'. Acta Neuropathologica. 2016. ↩︎
Baker et al. Cryo-EM structures of FTDP-17 tau filaments. Acta Neuropathologica. 2021. ↩︎