Tau Oligomers Resist Phase Separation.

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Tau protein facilitates microtubule stabilization and intracellular transport via liquid-liquid phase separation (LLPS).
• Aberrant Tau aggregation driven by LLPS is a hallmark of tauopathies, including Alzheimer's disease.
• The precise link between Tau's structural changes and its phase separation properties is not fully understood.

Purpose of the Study:

• To investigate how Tau oligomerization influences its liquid-liquid phase separation (LLPS) behavior.
• To differentiate the phase separation capabilities of monomeric, oligomeric, and amyloidogenic Tau species.
• To elucidate the role of Tau's structural state in its pathological aggregation and condensate formation.

Main Methods:

• Dynamic light scattering (DLS) to monitor Tau oligomer formation over time.
• Fluorescence microscopy to visualize and assess Tau phase separation and condensate formation.
• Thioflavin T (ThT) staining to characterize oligomer maturation stages.

Main Results:

• Tau monomers readily undergo LLPS to form condensates.
• Increasing Tau oligomerization progressively reduces its LLPS propensity, though oligomers can still phase separate less efficiently.
• Early-stage, ThT-negative Tau oligomers are recruited into condensates of younger Tau, while mature, ThT-positive oligomers are excluded.

Conclusions:

• Tau's structural state, particularly its oligomeric form, dynamically modulates its liquid-liquid phase separation (LLPS) behavior.
• The maturation stage of Tau oligomers dictates their interaction with existing Tau condensates, impacting aggregation pathways.
• Understanding the interplay between Tau LLPS and oligomerization is crucial for deciphering Tau pathogenesis and developing targeted therapies for tauopathies.