Alzheimer's disease is characterized by a progressive loss in neuronal volume, as well as an accumulation of abnormal proteins both inside (tau) and outside of neurons (Ab peptide). These proteins form amyloid fibers, which invade the inside and outside of neuronal cells and "smother" them until destroyed. These marks of the disease appear very early, but are difficult to detect. Researchers at the Institute of Structural Biology (IBS, Grenoble), in collaboration with the Institut Laue-Langevin (Grenoble), the Jülich Research Center, the Materials and Physical Engineering Laboratory (Grenoble) and the University of California, have demonstrated that the movement of water molecules could be an indirect marker of the presence of tau amyloid fibers.

This hypothesis is based on observations by neutron scattering, which is a spectroscopic technique capable of sensing hydrogen atoms and thus measuring the range in movement of water molecules on a nanoscale. First, the researchers artificially created fibers in vivo by adding heparan sulfate, a complex polysaccharide whose sulfate groups are known to trigger the aggregation of tau proteins between them. To observe the movement of water, the researchers had to "conceal" the hydrogen from the tau protein and the heparin sulfate, by exchanging it for one of its isotopes, deuterium. The researchers achieved the latter by using a technology recently developed by C.Laguri and H. Lortat-Jacob at the IBS, which can chemically sulfate a polysaccharide produced by bacterial fermentation in a deuterated medium. "We then compared the neutron scattering experiments on normal tau proteins to experiments on pathological fibers", says Martin Weik, team leader at the IBS. "In addition, we could discriminate the movements of water near the heart of the fiber from movements in the periphery, in a flexible structure known as a 'fuzzy coat'." The results show that water is much more mobile in amyloid fibers than non-aggregated tau proteins. "The acceleration concerns 25% of the water molecules", says Yann Fichou, first author of the publication. "And we have shown by molecular dynamics calculations that it takes place in the 'fuzzy coat' and not at the heart of the fiber." 

According to the researchers, the increased mobility of water molecules might affect the development of amyloid fibers by a so-called "entropic stabilization" effect. This thermodynamic effect might promote the aggregation of the tau protein at the expense of the normal (non-aggregated) and, a priori, more stable state. "The movement of water during the fiber formation process must now be followed", emphasizes Martin Weik. "It would be interesting to know whether the propensity to form these fibers could be modulated by the dynamics of water molecules."  

These results open up a new field of knowledge in the understanding of Alzheimer's disease. Indeed, this increased fluidity reveals the formation of pathogenic fibers, which could serve as an early marker of the disease. To advance this idea, the next step builds on the expertise of other researchers at the DSV, who developed a type of functional MRI based on the diffusion of water molecules. "We contacted the team of Denis Lebihan at the NeuroSpin", stated the IBS researchers. "We are going to collaborate together. This is a real opportunity to develop a novel diagnostic tool."