Structure-based inhibitors of tau aggregation.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Aggregated tau protein is implicated in over 20 neurological disorders, including Alzheimer's disease.
• Previous research identified tau segments VQIINK and VQIVYK as aggregation drivers, but VQIVYK-based inhibitors showed limited efficacy.
• Inhibitors targeting VQIVYK failed to prevent seeding by full-length tau fibrils.

Purpose of the Study:

• To identify the more potent tau aggregation-driving segment between VQIINK and VQIVYK.
• To elucidate the structural basis for the dominant tau aggregation mechanism.
• To develop novel inhibitors targeting the VQIINK segment for therapeutic intervention.

Main Methods:

• Utilized micro-electron diffraction, a cryo-electron microscopy technique, to determine the structures of the VQIINK segment.
• Designed and tested inhibitors based on the determined VQIINK structures.
• Assessed inhibitor efficacy in preventing full-length tau aggregation and seeding in HEK293 biosensor cells.

Main Results:

• The VQIINK segment was identified as the more potent driver of tau aggregation.
• Two distinct structures of the VQIINK segment were resolved, explaining its dominant role.
• Developed inhibitors effectively inhibited tau aggregation and prevented exogenous full-length tau fibrils from seeding amyloid formation in cells.

Conclusions:

• The VQIINK segment's structures provide critical insights into tau aggregation mechanisms.
• Novel inhibitors targeting VQIINK demonstrate significant therapeutic potential for tauopathies.
• The identified VQIINK structures may represent distinct tau amyloid polymorphs, potentially explaining prion-like tau strains.