Reversibility and β-sheet formation are decoupled in tau condensate aging

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Neurofibrillary tangles (NFTs) composed of tau protein are hallmarks of Alzheimer's disease (AD) and correlate with cognitive decline.
• Biomolecular condensates of tau are early intermediates in aggregation, potentially facilitating pathological assembly in AD, ALS, and FTD.
• The transition from reversible tau condensates to irreversible, pathogenic aggregates remains mechanistically unclear.

Purpose of the Study:

• To investigate the phase behavior, structural transitions, and thermodynamic reversibility of tau during condensate aging.
• To elucidate the molecular basis of tau condensate evolution into irreversible aggregates.
• To determine if β-sheet enrichment and irreversible aggregation are coupled processes in tau pathology.

Main Methods:

• Mapping tau phase behavior during condensate aging.
• Analyzing structural transitions and thermodynamic reversibility of tau species.
• Characterizing tau intermediates using biophysical techniques (details not specified in abstract).

Main Results:

• Tau condensate aging involves distinct rates for β-sheet enrichment and irreversible aggregation, indicating they are mechanistically uncoupled.
• Identified β-sheet-rich tau condensates that are thermodynamically reversible.
• Discovered irreversible tau aggregates that lack β-sheet structure, challenging linear aggregation models.
• Revealed a diverse landscape of tau intermediates with varying structural and thermodynamic properties.

Conclusions:

• The pathological end state of tau aggregation is not a simple linear progression.
• Decoupling of structure (β-sheet content) and irreversibility in tau aggregates has significant implications for understanding neurodegenerative disease mechanisms.
• These findings offer potential new targets for therapeutic interventions aimed at preventing or reversing tau pathology.