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In Vitro Assay for Studying the Aggregation of Tau Protein and Drug Screening
Published on: November 20, 2018
Human Tau isoforms assemble into ribbon-like fibrils that display polymorphic structure and stability
Susanne Wegmann1, Yu Jin Jung2, Subashchandrabose Chinnathambi3
1Department of Biosystems Science and Engineering, ETH Zürich, CH-4058 Basel, Switzerland.
The Journal of Biological Chemistry
|June 23, 2010
Summary
Alzheimer disease fibrils formed by Tau protein show structural diversity, challenging existing models. These Tau protein fibrils disassemble into building blocks under stress, highlighting the role of hydrophobic and electrostatic interactions.
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- Tau protein aggregates into fibrous structures, forming characteristic lesions in Alzheimer disease.
- Understanding the precise structure of Tau fibrils is crucial for elucidating disease mechanisms.
Purpose of the Study:
- To investigate the structural polymorphism of fibrils assembled from different human Tau isoforms and domains.
- To challenge and refine current structural models of paired helical filaments.
Main Methods:
- High-resolution atomic force microscopy (AFM) and electron microscopy (EM).
- Analysis of fibrils assembled from various human Tau isoforms and domains.
Main Results:
- Observed structural polymorphism in Tau fibrils, including "thin twisted," "thin smooth," and "thick" fibrils.
- "Thick fibrils" resemble heavily twisted ribbons, challenging paired helical filament models.
- Tau fibrils exhibit axial subperiodicities and disassemble into uniform fragments under stress, driven by hydrophobic and electrostatic interactions.
Conclusions:
- Current structural models of paired helical filaments require revision based on observed fibril polymorphism.
- Fibril integrity is governed by hydrophobic and electrostatic interactions, with fragments acting as structural building blocks.
- The flexible N- and C-termini of Tau protein are largely invisible to AFM and EM in fibril structures.
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