Aug 5 2020
A common feature of several neurodegenerative diseases such as Alzheimer’s is the agglomeration of proteins into structures known as amyloid plaques.
Developing non-pharmaceutical approaches is important since there are no existing drugs to slow or reverse the cognitive impairment in neurodegenerative disease like Alzheimer’s. The ability to use infrared lasers to dissociate amyloid fibrils opens up a promising approach. Image Credit: Tokyo University of Science.
Using simulations and experiments, researchers have now demonstrated how resonance with an infrared laser, tuned to a particular frequency, leads to the disintegration of amyloid fibrils from the inside out.
The study results pave the way for novel therapeutic potentials for amyloid plaque-related neurodegenerative diseases that could not be cured so far.
A prominent characteristic of various neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, is the development of damaging plaques that include aggregates—also called fibrils—of amyloid proteins.
Sadly, even after several years of research, it has been extremely challenging to get rid of such plaques. Therefore, the treatment options that can be availed by patients with such disorders are restricted and are less effective.
Recently, in contrast to taking the chemical route with the use of drugs, a few researchers have opted for alternative methods, such as ultrasound, to eliminate amyloid fibrils and stop the progress of Alzheimer’s disease.
A research group, under the guidance of Dr Takayasu Kawasaki (IR-FEL Research Center, Tokyo University of Science, Japan) and Dr Phuong H. Nguyen (Centre National de la Recherche Scientifique, France), with contributions of other researchers from the Aichi Synchrotron Radiation Center and the Synchrotron Radiation Research Center, Nagoya University, Japan, has employed novel techniques to reveal how infrared-laser irradiation can eliminate amyloid fibrils.
In a paper published recently in the Journal of Physical Chemistry B, the researchers describe the findings of molecular dynamics simulations and laser experiments. A two-pronged attack on the issue was essential due to the inherent restrictions of every method.
While laser experiments coupled with various microscopy methods can provide information about the morphology and structural evolution of amyloid fibrils after laser irradiation, these experiments have limited spatial and temporal resolutions, thus preventing a full understanding of the underlying molecular mechanisms.
Takayasu Kawasaki, IR-FEL Research Center, Tokyo University of Science
Kawasaki added, "On the other hand, though this information can be obtained from molecular simulations, the laser intensity and irradiation time used in simulations are very different from those used in actual experiments. It is therefore important to determine whether the process of laser-induced fibril dissociation obtained through experiments and simulations is similar.”
The researchers utilized a portion of a yeast protein that forms amyloid fibrils on its own. As part of the laser experiments, the researchers tuned the frequency of an infrared laser beam to that of the “amide I band” of the fibril, thereby developing resonance.
From the scanning electron microscopy images, it was confirmed that the amyloid fibrils disintegrated upon laser irradiation at the resonance frequency, and a combination of different spectroscopy methods demonstrated the ultimate structure following fibril dissociation.
The researchers performed the simulations by using a method known as “nonequilibrium molecular dynamics (NEMD) simulations,” which was already used by a few members of the present group.
The results obtained using this method confirmed those of the experiment and also validated the complete amyloid dissociation process down to highly particular details.
With the help of simulations, the team noted that the process starts at the core of the fibril, where the resonance splits up the intermolecular hydrogen bonds and divides the proteins in the aggregate. The disruption to this structure then spreads externally to the ends of the fibril.
The experiment and simulation collectively make a good model for an innovative treatment potential for neurodegenerative disorders.
In view of the inability of existing drugs to slow or reverse the cognitive impairment in Alzheimer’s disease, developing non-pharmaceutical approaches is very desirable. The ability to use infrared lasers to dissociate amyloid fibrils opens up a promising approach.
Takayasu Kawasaki, IR-FEL Research Center, Tokyo University of Science
The ultimate aim of the team is to determine a framework that integrates laser experiments with NEMD simulations to explore the process of fibril dissociation in a highly detailed manner, and new studies are already ongoing. It is hoped that all such measures will offer a ray of hope for those dealing with Alzheimer’s or other neurodegenerative diseases.
Journal Reference
Kawasaki, T., et al. (2020) Infrared Laser-Induced Amyloid Fibril Dissociation: A Joint Experimental/Theoretical Study on the GNNQQNY Peptide. Journal of Physical Chemistry B. doi.org/10.1021/acs.jpcb.0c05385.