Tau Filament Structures Resolved by Cryo-EM

Overview

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.

Historical Context: From Electron Microscopy to Cryo-EM

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.

Tau Isoforms and Filament Composition

3R vs 4R Tau

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:

Cryo-EM Structures in Alzheimer’s Disease

Paired Helical Filaments (PHFs)

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:

• Cross-β sheet architecture: The filament core is composed of β-strands running perpendicular to the filament axis

• Residues 306–378: The core encompasses residues from the microtubule-binding repeat region (R1–R4)

• Dimeric structure: Two tau molecules form a dimer through a disulfide bond at Cys322

• Hexapeptide motifs: Two hexapeptide sequences (^306VQIVYK^311 and ^378VQIINK^383) form β-strands that drive aggregation

Straight Filaments (SFs)

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.

Silver-Colloid Positive Filaments (SCs)

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.

Cryo-EM Structures in Corticobasal Degeneration

CBD-Specific Filament Conformations

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:

1. CBD-type PHFs: Filaments with a C-shaped core similar to AD but with different protofilament arrangement

2. CBD-type straight filaments: Straight filaments with distinct structural features

3. 4R tau dominance: The filaments are composed primarily of 4R tau isoforms

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.

Cryo-EM Structures in Progressive Supranuclear Palsy

PSP-Specific Filament Conformations

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:

1. PSP-type PHFs: Similar overall fold to CBD but with subtle structural differences in the protofilament interface

2. Ribbon-like filaments (RLs): A unique filament morphology observed in PSP, composed of two C-shaped protofilaments arranged in a ribbon conformation

3. 4R tau dominance: Like CBD, PSP filaments are primarily composed of 4R tau isoforms

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.

Structural Comparison: Disease-Specific Tau Filaments

flowchart TD
    A["Tau Protein"]  -->  B["Alternative Splicing"]
    B  -->  C["3R Tau"]
    B  -->  D["4R Tau"]

    C  -->  E["AD PHFs"]
    C  -->  F["AD SCs"]
    D  -->  G["CBD PHFs/SFs"]
    D  -->  H["PSP PHFs/SFs/RLs"]

    E  -->  I["Cryo-EM Structures<br/>Revealed Disease-Specific<br/>Filament Conformations"]
    F  -->  I
    G  -->  I
    H  -->  I

    I  -->  J["Therapeutic Implications:<br/>Strain-Specific<br/>Aggregation Inhibitors"]

Key Structural Differences

Implications for Therapeutics

Strain-Specific Drug Development

The identification of disease-specific tau filament structures has important implications for therapeutic development:

1. Aggregation inhibitors: Drugs targeting tau aggregation must be designed to recognize the specific β-sheet conformations present in each disease

2. Antibody therapeutics: Anti-tau antibodies may have different efficacy depending on which tau strains are present

3. Small molecule stabilizers: Compounds that stabilize microtubules or prevent tau misfolding may have varying effects across tauopathies

Current Therapeutic Approaches

Based on the structural insights from cryo-EM, several therapeutic strategies are being pursued:

• Small molecule inhibitors: Compounds that bind to the hexapeptide motifs and prevent β-sheet formation

• Antisense oligonucleotides (ASOs): Drugs like NIO752 targeting MAPT mRNA to reduce tau production

• Immunotherapies: Active and passive immunization approaches targeting extracellular tau aggregates

See Also

• MAPT gene

• Tau Protein

• MAPT Gene

• 4R Tauopathy Mechanisms

• Tau Strain Diversity

• Corticobasal Degeneration

• Glial Tau Pathology in PSP and CBD

External Links

• PubMed

• KEGG Pathways

Related Pages

• Tau Protein

• MAPT Gene

• 4R Tauopathy Differential Biomarkers

• 4R Tauopathy Mechanisms

• Tau Strain Diversity

• Corticobasal Degeneration

• Glial Tau Pathology in PSP and CBD