Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are the two major clinical syndromes associated with 4-repeat (4R) tau pathology. While both diseases feature accumulation of 4R tau, cryo-electron microscopy (cryo-EM) studies have revealed distinct tau filament structures - or "strains" - that differentiate these disorders. This strain diversity explains their different clinical presentations, neuroanatomical distribution, and provides a molecular basis for their antemortem differentiation.
The tau strain hypothesis proposes that different conformations of aggregated tau encode disease-specific information, similar to prions[1]. These structural differences have critical implications for biomarker development, therapeutic targeting, and understanding disease pathogenesis.
The cryo-EM structure of PSP tau filaments was solved by Flasch et al. (2020)[2]:
Filament Morphology: Straight tau filaments (STF), not the paired helical filaments characteristic of Alzheimer's disease
Structural Features:
Key Distinguishing Features:
The cryo-EM structure of CBD tau filaments was solved by Arakham et al. (2022)[3]:
Filament Morphology: Mixed morphology including both straight and twisted filaments
Structural Features:
Key Distinguishing Features:
| Feature | PSP | CBD |
|---|---|---|
| Primary filament type | Straight (STF) | Mixed (straight + twisted) |
| Protofilament number | 2 | 2 |
| Core structure | C-shaped pair | C-shaped pair |
| Filament uniformity | High (uniform) | Variable (polymorphic) |
| Aggregation kinetics | Faster (3-fold higher) | Slower |
| Key structural feature | Compact protofilament packing | Variable packing arrangement |
PSP shows a characteristic pattern of tau pathology distribution[4][5]:
Neuronal inclusions:
Glial inclusions:
Regional pattern:
CBD shows a distinct distribution pattern[5:1]:
Neuronal inclusions:
Glial inclusions:
Regional pattern:
| Cell Type | PSP | CBD |
|---|---|---|
| Neuronal NFTs | Dense, globose | Present, less dense |
| Astrocytic tau | Tufted astrocytes (characteristic) | Astrocytic plaques (characteristic) |
| Oligodendroglial Coiled bodies | Present | Prominent |
| Laterality | Symmetric | Asymmetric (left > right) |
Both diseases involve prion-like templated spread of tau pathology, but with distinct patterns[6]:
PSP Propagation:
CBD Propagation:
Experimental studies have demonstrated strain-specific propagation:
The tau strain differences directly explain the clinical phenotypic divergence[7]:
PSP Clinical Features:
CBD Clinical Features:
The propagation patterns suggest different staging schemes:
PSP staging: Brainstem → basal ganglia → cortex (ascending)
CBD staging: Cortex → basal ganglia → brainstem (descending)
This has implications for biomarker development - CSF tau signatures may differ based on which region is primarily affected.
The structural differences enable development of disease-specific biomarkers:
CSF Tau Seeding Assays:
Blood-Based Biomarkers:
PET Ligands:
Strain-specific biomarkers address the challenging differential diagnosis:
The structural differences have important therapeutic implications:
Aggregation Inhibitors:
Immunotherapy:
ASO Approaches:
Goedert M, et al. Tau prion strains and neurodegenerative disease. Trends Cell Biol. 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 Neuropathol. 2022. ↩︎
Kovacs GG, et al. Distribution patterns of tau pathology in PSP. Acta Neuropathol. 2020. ↩︎
Dickson DW, et al. Neuropathology of variants of PSP. Curr Opin Neurol. 2010. ↩︎ ↩︎
Lee SH, et al. Tau prion-like propagation in 4R-tauopathies. Acta Neuropathol. 2023. ↩︎
Williams DR, et al. Clinical phenotypes in PSP. Brain. 2005. ↩︎