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. 2015 May 19;112(20):6365-70.
doi: 10.1073/pnas.1422824112. Epub 2015 Apr 27.

Hydration water mobility is enhanced around tau amyloid fibers

Yann Fichou  1 , Giorgio Schirò  2 , François-Xavier Gallat  2 , Cedric Laguri  2 , Martine Moulin  3 , Jérôme Combet  4 , Michaela Zamponi  5 , Michael Härtlein  3 , Catherine Picart  6 , Estelle Mossou  7 , Hugues Lortat-Jacob  2 , Jacques-Philippe Colletier  2 , Douglas J Tobias  8 , Martin Weik  1
Affiliations

Hydration water mobility is enhanced around tau amyloid fibers

Yann Fichou et al. Proc Natl Acad Sci U S A. .

Abstract

The paired helical filaments (PHF) formed by the intrinsically disordered human protein tau are one of the pathological hallmarks of Alzheimer disease. PHF are fibers of amyloid nature that are composed of a rigid core and an unstructured fuzzy coat. The mechanisms of fiber formation, in particular the role that hydration water might play, remain poorly understood. We combined protein deuteration, neutron scattering, and all-atom molecular dynamics simulations to study the dynamics of hydration water at the surface of fibers formed by the full-length human protein htau40. In comparison with monomeric tau, hydration water on the surface of tau fibers is more mobile, as evidenced by an increased fraction of translationally diffusing water molecules, a higher diffusion coefficient, and increased mean-squared displacements in neutron scattering experiments. Fibers formed by the hexapeptide (306)VQIVYK(311) were taken as a model for the tau fiber core and studied by molecular dynamics simulations, revealing that hydration water dynamics around the core domain is significantly reduced after fiber formation. Thus, an increase in water dynamics around the fuzzy coat is proposed to be at the origin of the experimentally observed increase in hydration water dynamics around the entire tau fiber. The observed increase in hydration water dynamics is suggested to promote fiber formation through entropic effects. Detection of the enhanced hydration water mobility around tau fibers is conjectured to potentially contribute to the early diagnosis of Alzheimer patients by diffusion MRI.

Keywords: amyloid fibers; hydration water; intrinsically disordered proteins; neutron scattering; tau protein.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Schematic representation of the tau isoform htau40 in its monomeric (Top) and fibrillated (Bottom) forms. The microtubule binding domain is roughly composed of the four repeat domains R1−R4 (residues 244–369) and the proline-rich domains P1 and P2. R1−R4 constitute the core domain, which forms cross-β structures as well as steric zippers in the fiber, whereas the rest of the protein is referred to as the fuzzy coat domain, which remains disordered in the fiber form. The amyloidogenic hexapeptide 306VQIVYK311 can be used as a model for the fiber core.
Fig. 2.
Fig. 2.
(A) Electron micrograph and (B) X-ray fiber diffraction pattern of deuterated tau amyloid fibers. The white arrows highlight the diffraction rings observed at 4.7 Å and 9.0 Å, which are characteristic of amyloid structures.
Fig. 3.
Fig. 3.
(A) MSD of the hydration water around monomers (D-tau-H2O) and fibers (D-fiber-H2O) of the tau protein. The MSD were extracted from the Gaussian approximation fitted between q values of 0.78 Å−1 and 1.76 Å−1. (B) Comparison of the raw QENS spectra of D-fiber-H2O and D-tau-H2O at 280 K, binned over q values from 0.45 Å−1 to 1.66 Å−1. The spectra of D-tau-H2O were extracted from Schiró et al. (29). For a visual comparison, the spectra were scaled with a multiplicative factor and corrected for a linear background. Because QENS spectra are symmetrical, the focus was put on positive energy exchange. (C) MSD of monomers (H-tau-D2O) and fibers (H-fiber-D2O) of the tau protein. They were extracted from the Gaussian approximation with a q4 correction between q values of 0.43 Å−1 and 1.93 Å−1. The error bars represent the SD output from the fitting procedure. Data on H-tau-D2O were taken from ref. and reanalyzed.
Fig. 4.
Fig. 4.
Dynamical properties of the hydration water around the fibrillated and the monomeric peptide 306VQIVYK311, obtained by MD simulations. (A) MSD of the first hydration shell (defined as water molecules within 3 Å of the peptide), (B) protein−water continuous HB correlation function (providing information on the timescale of water rotational/librational dynamics), and (C) protein−water intermittent HB correlation function (providing information on the timescale of the rearrangement of the protein−water HB network due to water translational diffusion).
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