Structures and Dynamics of Tau Assemblies from Solid-State NMR

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Aggregation of microtubule-associated protein tau into β-sheet fibrils is a hallmark of neurodegenerative diseases like Alzheimer's disease (AD).
• Understanding tau's structure and dynamics in various states (fibrillar, membrane-bound, microtubule-bound) is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To elucidate the structure and dynamics of different tau assemblies using solid-state NMR spectroscopy.
• To investigate the role of post-translational modifications (PTMs) and environmental conditions on tau fibril formation and structure.
• To explore the potential for in vitro reconstruction of AD-tau for therapeutic and diagnostic development.

Main Methods:

• Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy was employed to analyze various tau assemblies.
• In vitro fibrillization experiments were conducted using full-length tau and truncated constructs, with and without heparin.
• Phospho-mimetic mutations and varying environmental conditions (pH, temperature, ionic strength) were used to study tau structure.

Main Results:

• Heparin-induced tau fibrils exhibit homogeneous structures dependent on microtubule-binding repeats, differing from ex vivo structures.
• Phospho-mimetic mutations, particularly at the PHF1 epitope, induce a three-layered rigid core mimicking 4R tau in tauopathies, indicating PTM redundancy.
• Reproducible in vitro reconstruction of AD-tau fold was achieved, but full-length AD tau lacked seeding potency, suggesting fuzzy coat dynamics are essential for propagation.
• Cholesterol-rich membranes induce tau fibrils and membrane insertion, supporting a role in nucleation and transmission.
• The R' segment N-terminal to the PHF1 epitope is the highest-affinity microtubule-binding domain.

Conclusions:

• Solid-state NMR provides detailed insights into tau structures and dynamics across different assemblies, advancing understanding of tau aggregation mechanisms.
• The in vitro reconstruction of AD-tau fold offers a platform for developing diagnostics and therapeutics.
• Fuzzy coat dynamics, not just the rigid core, appear critical for prion-like propagation of tau aggregates.
• Lipid membranes play a role in tau nucleation and transmission.
• Targeting the R' segment may offer a strategy to inhibit tau aggregation.