Cryo-electron microscopy (cryo-EM) has revolutionized our understanding of the molecular basis of tauopathies by revealing the atomic structures of tau filaments extracted from human brain tissue. These studies have demonstrated that distinct tau filament conformations are associated with different neurodegenerative diseases, providing a structural foundation for understanding disease specificity and developing targeted therapeutics. This mechanism page summarizes the cryo-EM structures of tau filaments from Alzheimer's disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), highlighting the structural differences between 3-repeat (3R) and 4-repeat (4R) tau isoforms and their implications for disease pathogenesis.
Before cryo-EM, tau filaments were characterized using negative stain electron microscopy and biochemical methods. Paired helical filaments (PHFs) and straight filaments (SFs) were first described in AD brain in the 1960s, but the atomic details of their assembly remained unknown for decades. The development of cryo-EM and image processing methods by Sjors Scheres, Michel Goedert, and colleagues at the MRC Laboratory of Molecular Biology enabled the first atomic-resolution structures of amyloid filaments in 2017.
The MAPT gene encodes six tau isoforms in the adult human brain, generated by alternative splicing of exons 2, 3, and 10. Exclusion or inclusion of exon 10 produces isoforms with three (3R) or four (4R) microtubule-binding repeats. This alternative splicing is developmentally regulated—fetal brain expresses only 3R tau, while adult brain contains equal amounts of 3R and 4R tau.
The differential expression of 3R and 4R tau isoforms is a key determinant of filament structure and disease specificity:
| Disease | Primary Isoform | Filament Types |
|---|---|---|
| Alzheimer's Disease | 3R + 4R (PHFs), 3R (SCs) | PHFs, SFs, SCs |
| Corticobasal Degeneration | Primarily 4R | PHFs, SFs |
| Progressive Supranuclear Palsy | Primarily 4R | PHFs, SFs, RLs |
The first atomic-resolution structure of tau filaments was solved using cryo-EM in 2017 by Fitzpatrick et al. (2017), revealing the detailed molecular architecture of PHFs from AD brain. The core of the PHF fold consists of residues V306–V378 of the 2N4R tau isoform, forming a C-shaped dimer that stacks to create the characteristic helical appearance.
Key structural features of AD PHFs:
AD brain also contains straight filaments, which share a common core structure with PHFs but differ in their helical parameters. The cryo-EM structure of SFs shows a similar C-shaped fold, with the same residues (306–378) forming the filament core.
More recent cryo-EM studies have identified a third filament type in AD brain—the silver-colloid positive filament (SC). These filaments are distinguished by their staining properties and have been shown to be composed of 3R tau isoforms, in contrast to PHFs which contain both 3R and 4R tau.
In 2018, Falcon et al. reported the cryo-EM structures of tau filaments from CBD brain, revealing a distinct filament architecture compared to AD. The CBD filament structures showed:
The structural differences between AD and CBD filaments explain the pathological distinction between these diseases and suggest that different templated conformations (or "strains") of tau filaments underlie each disease.
Concurrent with the CBD studies, Falcon et al. (2018) also solved the structures of tau filaments from PSP brain. PSP filaments share some features with CBD but also exhibit distinct characteristics:
The identification of disease-specific filament structures supports the concept of tau strains—conformational variants of aggregated tau that are self-propagating and determine disease phenotype.
| Feature | AD | CBD | PSP |
|---|---|---|---|
| Primary isoform | 3R + 4R | 4R | 4R |
| Filament types | PHF, SF, SC | PHF, SF | PHF, SF, RL |
| Core residues | 306–378 | 304–378 | 304–378 |
| Protofilament count | 2 | 2 | 2 or 4 |
| Disease-specificity | High | High | High |
The identification of disease-specific tau filament structures has important implications for therapeutic development:
Based on the structural insights from cryo-EM, several therapeutic strategies are being pursued: