Progress in Alzheimer’s research: A German–Dutch team has recorded very sharp images of amyloid fibrils. The latter occur in the typical protein deposits in the brains of Alzheimer’s patients. Jülich biochemists headed by Dr. Lothar Gremer, junior professor Gunnar Schröder, and Prof. Dieter Willbold (pictured) are heavily involved in this research work.
Prof. Willbold, why are these images something special?
The fibrils are extremely thin: about 7 nanometres in thickness. No one had previously recorded such precise images of their three-dimensional structure. They show details that were hitherto unknown.
What is the advantage of seeing these details?
We can now better explain how the body’s own amyloid-beta proteins form the damaging deposits. And we are able to better understand how genetic factors influence the development of Alzheimer’s disease, for example by increasing or decreasing the stability of the amyloid fibrils. This is a milestone for science.
Does this have consequences for the treatment of Alzheimer’s?
Not immediately. But thanks to these data, we can develop active substances to combat the disease in a more targeted manner.
The interview was conducted by Christian Hohlfeld.
In addition to basic research, Jülich’s Institute of Complex Systems (ICS-6) is also developing a novel treatment strategy with its own candidate drug for Alzheimer’s disease. In autumn 2017, a spin-off company called Priavoid GmbH took to this task.
Alzheimer’s disease occurs when harmless protein molecules, called monomers, cluster together into harmful, toxic oligomers which damage the connections between nerve cells and ultimately the nerve cells themselves. The monomers are constantly produced inside us, without necessarily leading to the development of the disease. The formation of the toxic oligomers is rare and random, but becomes more and more likely over time. This is thought to be the reason why a person’s age is the strongest risk factor for Alzheimer’s disease.
The new drug candidate eliminates the toxic oligomers. It has now passed all required preclinical safety and toxicity tests and is about to be approved for phase I clinical trials. During this phase, the drug will be tested on healthy volunteers to investigate any undesirable side effects. On average, however, it takes about 7 years for a drug to be potentially approved for the market after the start of a phase I study.
Cryo-electron microscopy is a relatively new research method for determining the structure of protein molecules. Scientists have so far mainly used X-ray crystallography and nuclear magnetic resonance spectroscopy. Cryo-electron microscopy has particular advantages when it comes to investigating large structures composed of hundreds or thousands of proteins. This makes it a lot easier to understand how individual protein molecules assemble to form macrostructures that perform complex functions in a cell or, in the case of Alzheimer’s fibrils, are connected to diseases. For this method, the specimens are first dissolved in water, then flash frozen, and finally investigated with an electron microscope.
In 2015, cryo-electron microscopy was voted the research method of the year by the journal Nature Methods on the basis of the remarkable progress made. In 2017, the researchers Jacques Dubochet, Joachim Frank, and Richard Henderson received the Nobel Prize in Chemistry for developing the method. As the Nobel Prize committee states in the relevant press release, cryo-electron microscopy “both simplifies and improves the imaging of biomolecules. This method has moved biochemistry into a new era.”
Image: Forschungszentrum Jülich/Sascha Kreklau, Video: Forschungszentrum Jülich