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Related Experiment Videos

Tau aggregation is driven by a transition from random coil to beta sheet structure.

Martin von Bergen1, Stefan Barghorn, Jacek Biernat

  • 1Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, D-22607 Hamburg, Germany.

Biochimica Et Biophysica Acta
|December 24, 2004
PubMed
Summary

The tau protein, unfolded in its soluble state, aggregates into paired helical filaments (PHFs) in Alzheimer's disease. Specific sequences within the tau protein can transition to beta-sheet structures, driving PHF formation and disease pathology.

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Structural Biology

Background:

  • The microtubule-associated protein tau aggregates into paired helical filaments (PHFs), a hallmark of Alzheimer's disease.
  • Soluble tau protein is natively unfolded, contributing to its stability but posing questions about its physiological function in microtubule stabilization.

Purpose of the Study:

  • To review recent studies on how the unfolded tau protein adopts beta-sheet structures, leading to PHF formation.
  • To investigate the role of specific tau protein sequences and mutations in PHF aggregation.

Main Methods:

  • Analysis of tau protein structure and aggregation.
  • Review of studies utilizing circular dichroism (CD) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction.

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Main Results:

  • The microtubule-binding domain, containing three or four repeats, is crucial for PHF formation and is unfolded in the soluble state.
  • Two hexapeptides within this domain are key for PHF building and can undergo a random coil to beta-sheet conformational change.
  • Mutations like P301L and DeltaK280 accelerate tau aggregation, highlighting the significance of these hexapeptides.

Conclusions:

  • The transition of specific tau protein sequences to beta-sheet structures is fundamental to PHF formation.
  • This conformational change is characteristic of amyloidogenic proteins and underlies PHF properties like resistance to degradation and Congo red binding.
  • Aggregated PHFs, both in vitro and in vivo, exhibit significant beta-sheet structure.