Structure-specific Mini-Prion Model for Alzheimer's Disease Tau Fibrils

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Tau protein fibrils adopt disease-specific structures in various tauopathies.
• Generating synthetic fibrils with hallmark structures is crucial for developing diagnostics and therapeutics.
• Alzheimer's Disease (AD) and Chronic Traumatic Encephalopathy (CTE) are major tauopathies.

Purpose of the Study:

• To rationally design synthetic tau fibrils that mimic disease-specific structural motifs.
• To investigate the seeding competency and templating capabilities of these synthetic fibrils.
• To establish a novel strategy for creating pathological tau fibril models.

Main Methods:

• Rational design of short peptides to adopt critical structural motifs of tauopathy fibrils.
• In vitro and cell-based seeding assays using tau biosensor cells.
• Double Electron-Electron Resonance (DEER) studies to confirm structural preservation across seeding generations.

Main Results:

• Developed synthetic mini-prions with exquisite seeding competency for tau constructs.
• Demonstrated that mini-AD prions catalyze the generation of AD and CTE-like fibril structures.
• Confirmed structural preservation of AD-like folds across multiple seeding generations via DEER.
• Showcased the dominance of templating effects over salt composition in fibril formation.

Conclusions:

• Mini-AD prions serve as potent catalysts with templating capabilities for generating pathological tau fibril models.
• This approach offers a novel strategy for designing synthetic tau fibrils that mimic disease-specific structures.
• The developed synthetic fibrils can serve as targets for diagnostic and therapeutic strategies in tauopathies.