Biphasic modulation of tau liquid-liquid phase separation by polyphenols

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Tauopathies are neurodegenerative diseases linked to abnormal tau protein aggregation.
• Liquid-liquid phase separation (LLPS) of tau is a key process in the development of tau pathology.
• Targeting tau LLPS is a promising therapeutic strategy for tauopathies.

Purpose of the Study:

• To identify small molecules that modulate tau liquid-liquid phase separation (LLPS).
• To investigate the effect of polyphenols on tau LLPS.
• To evaluate gallic acid (GA) as a potential therapeutic agent for tauopathies.

Main Methods:

• Screening of various polyphenols for their effect on tau LLPS.
• Characterization of the concentration-dependent biphasic modulation of tau LLPS by gallic acid (GA).
• Assessment of GA's impact on the liquid-to-gel transition in tau condensates and fibril formation.

Main Results:

• Gallic acid (GA) demonstrated a concentration-dependent biphasic modulation of tau LLPS.
• GA expedited the liquid-to-gel transition in tau condensates.
• GA effectively inhibited the formation of pathological fibrillar tau aggregates.

Conclusions:

• Gallic acid (GA) is a potent modulator of tau liquid-liquid phase separation (LLPS).
• GA's ability to accelerate condensate transitions and inhibit fibril formation suggests therapeutic potential for tauopathies.
• Further research into GA and similar polyphenols could lead to novel treatments for neurodegenerative diseases.