Investigating the Single-Fibril Growth Dynamics of Tau in a Heterogeneous Aggregation Landscape

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Tau protein aggregation into distinct polymorphs is linked to specific tauopathies.
• Monitoring single aggregate formation is crucial for understanding tau aggregation mechanisms.

Purpose of the Study:

• To investigate the real-time formation and characteristics of tau aggregates in the presence of polyU RNA.
• To differentiate between nanoaggregate and fibril formation pathways and kinetics.

Main Methods:

• Total internal reflection fluorescence microscopy (TIRFM) for real-time monitoring.
• Electron microscopy and circular dichroism spectroscopy for structural analysis.
• Kinetic analysis of nucleation and growth rates.

Main Results:

• TIRFM revealed novel nanoaggregates alongside conventional amyloid fibrils.
• Nanoaggregates exhibit nucleation-dependent formation with slow growth (<20 nm/h), while fibrils show faster elongation (3-4 μm/h).
• Nanoaggregates are spherical (≈20 nm), beta-sheet rich, stable, and inhibited by salts, unlike fibrils.

Conclusions:

• Tau-polyanion nanoaggregates, stabilized by electrostatic, H-bonding, and hydrophobic interactions, may form intracellularly.
• These nanoaggregates could act as seeds for tau fibril proliferation in vivo.
• Understanding these distinct aggregation pathways is vital for tauopathy research.