Alzheimer’s disease markers could be identified through protein water mobility

27.04.2015

• One of the pathological hallmarks of Alzheimer’s disease is the formation of amyloid fibres by tau proteins 
• Results have shown that water mobility is increased on the surface of these tau fibres, suggesting a potential avenue for the identification of Alzheimer’s disease markers

A study of water mobility on the surface of tau protein fibres has been conducted by a global team of scientists using neutron scattering experiments at the Institut Laue-Langevin (ILL) in Grenoble, France and the Jülich Centre for Neutron Science at the Heinz Maier-Leibnitz-Zentrum (MLZ) in Garching, Germany. The team, led by IBS scientists, found water mobility on the surface of tau protein fibres is increased; the findings, reported in PNAS (Proceedings of the National Academy of Sciences of the United States of America), suggest that the movement of water molecules could be a marker for the presence of amyloid tau fibres and contribute to the detection of Alzheimer’s disease.

The accumulation of individual tau protein molecules into amyloid fibres occurs in a variety of neuro-degenerative diseases, damaging the neurons and preventing effective cognitive functions and mental abilities. “Amyloid fibres develop as the intrinsically disordered individual tau proteins aggregate, forming a fibre core surrounded by a so-called ‘fuzzy coat’”, explains Dr. Jacques-Philippe Colletier, a co-author on the study. "These pathological fibres develop early on in Alzheimer’s disease and understanding the mechanism by which tau aggregates is integral to understanding the disease’s development and progression.” 

The team measured and compared the mobility of water molecules on the surface of non-aggregated tau monomers and tau fibres. This was done by carrying out neutron scattering experiments on tau that had been deuterated (whereby all hydrogen atoms are replaced by atoms of its isotope deuterium) at the ILL and the MLZ, international research centres at the leading edge of neutron science and technology that provided the high flux of neutrons needed to probe and record the dynamics of water molecules on the surface of tau. Fibre formation was triggered by adding heparane sulphate which was also deuterated, a technique developed at the Institut de Biologie Structurale (IBS) in Grenoble. 

Dr Martin Weik, also a co-author on the study, said: “This study perfectly illustrates the benefits of using neutrons in probing the dynamics of biological samples. This spectroscopic technique allowed us to measure the mobility of water molecules on tau surfaces with high accuracy.” 

Protein deuteration was used to largely mask the neutron scattering signal of the proteins themselves, and focus instead on the signal from the water molecules on the protein surfaces. Drs Yann Fichou and Giorgio Schirò of the research team were surprised to observe that the amyloid fibres formed after tau aggregation showed enhanced water mobility in their vicinity compared to non-aggregated tau proteins, and explained the additional steps taken. “The experimental result was further refined by carrying out molecular dynamics simulations, suggesting that it is the mobility of water on the surface of the ‘fuzzy coat’ of tau sticking out of the fibre core that is increased.”

The ensemble of results suggests that methodologies sensitive to the diffusion of water, such as diffusion magnetic resonance imaging, could be used to detect increased water mobility in Alzheimer-diseased brains.

Instrument:   IN16B - Backscattering spectrometer

Ref.:PNAS, doi: 10.1073/pnas.1422824112

Fichou Y., Schirò G., Gallat F.-X., Laguri C., Moulin M., Combet J., Zamponi M., Härtlein M., Picart C., Mossou E., Lortat-Jacob H., Colletier J.-P., Tobias D., Weik M. (2015) Hydration water mobility is enhanced around tau amyloid fibers.

Notes to editors

About ILL – The Institut Laue-Langevin (ILL) is an international research centre based in Grenoble, France. It has led the world in neutron-scattering science and technology for more than 40 years, since experiments began in 1972. ILL operates one of the most intense neutron sources in the world, feeding beams of neutrons to a suite of 40 high-performance instruments that are constantly upgraded. Each year 1,200 scientists from more than 30 countries worldwide visit ILL (2000 visits), to conduct research into condensed matter physics, (green) chemistry, biology, nuclear physics, and materials science. The UK, along with France and Germany, is an Associate and major funder of the ILL.

About the IBS - The Institut de Biologie Structurale (IBS) is a research centre in structural biology. The IBS performs interdisciplinary research at the interface of biology, physics and chemistry, and combines:

• fundamental research
• technical innovation
• hosting of scientists
• training of young researchers
• a site that facilitates access to European research institutes

The IBS employs approximately 230 people.